. _:b414677043 . _:b414676520 . _:b6102613 . _:b414677042 . _:b414676985 . _:b6102614 . _:b414677107 . _:b414677053 . _:b6102615 . _:b414677052 . _:b6102608 . _:b414677138 . _:b414677055 . _:b414677511 . _:b6102609 . . _:b414677054 . _:b6102610 . _:b414677280 . . _:b414677049 . _:b6102611 . . _:b414677048 . . _:b6102620 . . _:b414677051 . _:b6102621 . . _:b414677050 . . _:b6102622 . _:b414677061 . _:b6102639 "During the process of T cell activation the duration of T cell-DC contacts is highly variable in vivo, ranging from minutes to several hours >>39<<. Early reports suggested that initial interactions during the first phase of T cell activation tend to be transient [5-10 minutes during the first 3-15 hours 20,21,40]. However, a more recent report found that long lived T cell-DC" . _:b414677894 . _:b6102623 . _:b414677060 . _:b6102616 . _:b414677063 . _:b6102617 . _:b6102632 "molecule and cytokine expression, cells were labeled with predetermined optimal antibody concentrations according to the manufacturer's staining protocol and 0.5 \u00D7 106 events in the CD4+ gate were acquired, as described previously >>10<<. Data acquisition was performed on an LSRII flow cytometer and analyzed using FACSDiva software (Becton Dickinson)." . _:b414677062 . . _:b6102618 . . _:b414677057 . _:b6102619 . _:b414677056 . _:b6102628 . _:b414677059 . . _:b6102629 . _:b414676938 . _:b414677058 . _:b6102630 . _:b414676939 . _:b414677069 . . _:b6102631 . . _:b414677068 . . _:b6102624 . _:b414677515 . _:b414677690 . _:b414677071 . _:b6102625 . _:b414677070 . . _:b6102626 . . _:b414677065 . _:b414677822 . _:b6102627 . _:b414677064 . . _:b414676684 . _:b6102636 . _:b414677067 . . _:b6102637 . _:b414677066 . _:b414676899 . . _:b6102638 . _:b414676683 . _:b414677432 . _:b414677023 . _:b414677077 . _:b6102639 . _:b414677076 . _:b6102632 . _:b414677079 . _:b414677235 . _:b414676561 . _:b6102633 . . _:b414677078 . . _:b6102634 . _:b414677073 . _:b414676525 . _:b6102635 . _:b414677586 . _:b414677072 . . _:b414676697 . _:b6102644 . _:b414676728 . . _:b414677075 . _:b6102645 . _:b414677074 . . _:b6102646 . . _:b414677085 . . _:b6102647 . . . _:b414677084 . _:b414676470 . _:b6102640 . _:b414677087 . . . _:b6102641 . _:b414677086 . _:b414677428 . _:b6102642 . _:b414676951 . _:b414677081 . _:b6102643 . _:b414677080 . . _:b414677041 . _:b6102652 . _:b414677083 . _:b6102653 . _:b414677082 . . . _:b6102654 . _:b414677093 . _:b414677239 . _:b6102655 . _:b414676767 . _:b6102618 "Tolerized T cells did not exhibit Er phoksphorylation after in vivo APC engagement >>36<<-38 (Fig. 5e). In contrast, treatment with anti-PD-L1 but not isotype control antibody during exposure of the tolerized T cells to antigen-bearing APCs resulted in substantial Erk phosphorylation in tolerized T cells (Fig. 5f). These" . _:b414677092 . _:b6102648 . . _:b414677095 . _:b414677250 . _:b6102649 . _:b414677549 . _:b414677752 . _:b414677094 . _:b6102650 . _:b414677089 . _:b6102651 . _:b414677088 . _:b414677705 . _:b6102660 . _:b414677091 . _:b414677188 . _:b6102661 . . _:b414677090 . _:b414677367 . _:b6102662 . _:b414677101 . . . _:b414676828 . _:b414677100 . _:b414676391 . _:b6102656 . _:b414676688 . _:b414677103 . . _:b414676631 . . _:b6102657 . _:b414677102 . _:b6102658 . _:b414677097 . . _:b6102659 . . _:b414677096 . _:b414677669 . _:b414677099 . _:b414676318 . _:b414677098 . _:b414676393 . _:b414677109 . _:b414677108 . . _:b414677111 . _:b414677621 . _:b414677626 . _:b414677110 . . . _:b414677105 . _:b414677104 . . _:b414677107 . . . _:b414677565 . _:b414677106 . _:b6102600 "Previous work demonstrated that TCR-induced calcium signals are associated with T cell motility and stable interactions with APCs >>25<<. BDC2.5 T cells isolated from p31-SP-tolerized, but not SHAM-SP-injected mice, did not flux calcium in response to strong secondary TCR stimulation with anti-CD3 (Fig. 1b). Furthermore, phosphorylation of the TCR \u03B6-chain and the MAP" . . _:b414677005 . . _:b414677117 . . . _:b414677116 . . _:b414677119 . _:b414676936 . . _:b414677118 . . _:b414677113 . _:b414677517 . . _:b414677112 . _:b414677214 . _:b414677115 . . . _:b414677114 . _:b414677227 . . _:b414676817 . _:b414677125 . _:b414677557 . _:b414676849 . _:b414677641 . _:b414677124 . _:b414677700 . _:b414677888 . _:b414677064 . _:b414677127 . _:b414676615 . _:b414677126 . _:b414677577 . _:b414676810 . _:b414677121 . _:b414676653 . _:b414677729 . _:b414677120 . . _:b414677123 . . _:b414677122 . . _:b414676542 . _:b414677133 . _:b414677704 . _:b414677559 . _:b414677132 . . _:b414677155 . _:b414676669 . . _:b414677135 . _:b414677104 . _:b414677134 . _:b414677873 . _:b414677314 . _:b414677015 . . . _:b414677129 . . . _:b414677128 . _:b414677550 . _:b414677131 . _:b414676764 . . _:b414677130 . . . . _:b414677141 . _:b414677140 . . _:b414676995 . _:b414677143 . _:b414677368 . . _:b414677142 . _:b414677592 . _:b414677137 . . _:b414677136 . _:b414677139 . _:b414677896 . _:b414677138 . _:b414677410 . _:b414677580 . _:b414677149 . . _:b414677148 . _:b414677362 . _:b414677151 . _:b414677150 . _:b414677747 . _:b414677145 . . _:b414677525 . _:b414677144 . _:b414676855 . . _:b414676429 . _:b414677147 . _:b414677146 . _:b414677157 . _:b414676497 . . _:b414677156 . _:b414677351 . _:b414677159 . _:b414677089 . . _:b414677158 . _:b414676990 . _:b414677071 . _:b414676716 . _:b414677153 . _:b414677004 . _:b414677152 . . _:b414676538 . _:b414677155 . . _:b414677154 . _:b414676415 . _:b414676486 . . _:b414677165 . _:b414677365 . _:b414677164 . . . . _:b414677167 . . _:b414677166 . _:b414677161 . . _:b414677269 . _:b414677620 . _:b414677160 . _:b414677452 . _:b414677163 . . _:b414677162 . . _:b414677837 . _:b414676988 . _:b414677051 . _:b414676298 . . _:b414677173 . . _:b414676799 . _:b414677027 . _:b414677172 . _:b414677608 . _:b414677175 . _:b414677575 . . _:b414677174 . . _:b414677169 . . _:b414677726 . _:b414677168 . . . _:b414677171 . . _:b414677170 . . _:b414677763 . _:b414677181 . _:b6102602 . _:b414677180 . . _:b414677183 . _:b414677569 . . . _:b414677182 . _:b414677177 . _:b414677478 . _:b414677473 . . _:b414677329 . _:b414677176 . . _:b414677179 . _:b414677095 . _:b414677017 . _:b414677178 . _:b414677148 . _:b6102593 "TCR ligation results in \u2018stop signals\u2019 that decrease T cell motility and are required for stable T cell-DC conjugate formation and development of the immunological synapse >>21<<,26. Prolonged T cell-DC interactions are critical for full T cell activation, proliferation and cytokine production 27-29. However, T cell movement and velocity during the long term maintenance of tolerance has not been well described." . _:b414677189 . _:b414676892 . _:b414677188 . . _:b414677191 . . _:b414677190 . . _:b414677168 . _:b414677507 . . _:b414677185 . _:b414677123 . _:b414677184 . _:b414676592 . _:b414677187 . . . _:b414677186 . _:b414677134 . _:b414677149 . _:b414677197 . . . _:b414677196 . . _:b414677199 . _:b414677819 . _:b414677198 . _:b414677686 . _:b6102623 . . . _:b414677193 . _:b414676511 . _:b414677360 . _:b414677192 . . . _:b414677195 . _:b414677194 . _:b414677205 . _:b414677204 . . _:b414677096 . _:b414677207 . _:b414676591 . _:b414676876 . _:b414677206 . _:b414677201 . . _:b414677200 . _:b414677203 . _:b414677761 . _:b414677164 . _:b414677202 . . _:b414677024 . . _:b414677213 . _:b414676496 . . _:b414676890 . _:b414677212 . . _:b414677215 . . _:b414677214 . _:b414676398 . _:b414677209 . _:b414677437 . . _:b414677208 . _:b414677012 . _:b414677211 . _:b414677778 . _:b414677210 . _:b414677221 . _:b414677220 . _:b414676987 . _:b414677784 . _:b414677223 . . _:b414677222 . _:b414676731 . _:b414677217 . . _:b414677216 . _:b414677219 . _:b414677438 . _:b414677218 . _:b414677229 . _:b414677191 . _:b414677228 . _:b414676831 . _:b414677231 . _:b414676931 . _:b414676425 . _:b414677230 . . _:b414677225 . . . _:b414677224 . . _:b414677227 . . _:b414677226 . _:b6102650 "Upon PD-L engagement, PD-1 can bind SH2-domain containing tyrosine phosphatase 1 (SHP-1) and SHP-2 4,>>43<<. The binding of SHP-1 and SHP-2 can terminate early TCR signals by dephosphorylating key signaling intermediates including the kinases Akt, PI3K, ZAP-70, and PKC-\u03B8. Like PD-1, CTLA-4 can interact with SHP-1 and SHP-2 14. Unlike PD-1," . _:b414677237 . _:b414677680 . _:b414677488 . _:b414677236 . . _:b414677239 . . . _:b414677238 . _:b414677057 . _:b414677233 . . _:b414676780 . _:b414677232 . . _:b414677235 . _:b414677316 . _:b414677234 . _:b414677245 . _:b414677481 . . _:b414677244 . _:b414677482 . _:b414677247 . _:b414677246 . . _:b414677241 . _:b414677240 . _:b414676478 . _:b414677243 . _:b414677242 . _:b6102627 . . . . _:b414676762 . . _:b414676624 . _:b414677356 . . _:b414677667 . . _:b414676698 . _:b414677183 . _:b414676507 . . _:b414677193 . _:b414677345 . _:b414677145 . . . _:b414677216 . . . . _:b414676431 . . . _:b414676462 . . _:b414677840 . _:b414676972 . _:b6102604 "2a and Supplementary Movie 2), similar to what has been observed in antigen non-bearing LN >>31<<." . _:b414676894 . . _:b414677732 . . . . _:b414677219 . . _:b414676992 . . _:b414677443 . . _:b414677289 . . _:b414677564 . _:b414677179 . _:b6102657 "Two recent reports investigated the role of CTLA-4 on T cell stop signals 44,>>45<<. One study found that CTLA-4 positive T cells failed to stop or slow down in response to in vivo peptide challenge, and anti-CTLA-4 increased T cell motility 44." . . _:b414676639 . . . _:b414676858 . _:b6102597 "Insulin-coupled, ethylene carbodiimide (ECDI) fixed APCs have a profound effect on the development of spontaneous type 1 diabetes (T1D) in the non-obese diabetic (NOD) mouse >>10<<. A single injection of the antigen-pulsed fixed splenocytes prevents and even reverses T1D after disease onset." . . . _:b414676345 . . _:b414677484 . _:b414677394 . . _:b414676886 . _:b414677342 . _:b414676761 . _:b414677671 . _:b414677687 . . _:b414676402 . _:b414677746 . . . . _:b414676722 . . . _:b414677463 . . _:b414677876 . . . . _:b414676736 . _:b414677222 . _:b6102662 "Finally, it is interesting to note that PD-1-PD-L1 blockade resulted in increased accumulation and/or enhanced proliferation of antigen-specific T cells within the target tissue >>10<<. This finding supports a key role for T cell-DC interactions during tissue-specific reactivation." . _:b414676789 . . _:b414676815 . . . . . . . _:b414676891 . _:b414677865 . _:b414676500 . . . _:b414676361 . . _:b414676844 . _:b414676733 . _:b414676352 . . . _:b414677157 . . _:b414676611 . . _:b414677691 . . . _:b414677048 . . . . _:b414677352 . . . . . . _:b414677169 . . _:b414677721 . . . . . _:b6102617 "1) and Erk phosphorylation 10,>>36<<. However, treatment of anergic T cells with PMA and ionophore can reverse tolerance and promote T cell activation (Fig." . . _:b414677311 . _:b414677102 . . _:b414677771 . . _:b414677750 . . _:b414677140 . . . . _:b414676447 . _:b414677790 . . _:b414677441 . _:b414677711 . _:b414677363 . . . _:b414677144 . . . _:b414676556 . _:b414677453 . _:b414677693 . . _:b414677884 . _:b414677710 . . _:b414676549 . . . . . _:b414677730 . . _:b6102605 "As PD-L1, but not PD-L2, is required for the maintenance of tolerance, we injected PD-L1-blocking antibodies >>10<<. PD-L1 blockade led the tolerant T cells to slow and swarm with a velocity of 1.4 \u00B1 0.1 \u03BCm/min, as compared to the 5.2 \u03BCm/min velocity observed after isotype control antibody treatment (P<0.0001) (Fig. 2a and Supplementary Movie 3). PD-1" . . . . . . . . _:b414677287 . _:b6102616 "1) and Erk phosphorylation >>10<<,36. However, treatment of anergic T cells with PMA and ionophore can reverse tolerance and promote T cell activation (Fig." . _:b414676580 . . . . _:b414676801 . _:b414677466 . _:b414676930 . . _:b414677325 . . . . . . . _:b414677521 . . . _:b414676659 . _:b414677777 . . _:b414676514 . _:b414676657 . . . . . _:b414677279 . _:b414676483 . . . . _:b414676852 . . _:b414676319 . . . _:b414676880 . _:b414676720 . _:b6102619 "Ag-SP tolerance resulted in a decrease in inflammatory cytokines including IL-2 and IFN-\u03B3 within the PLN >>10<<. Here we bred antigen-specific NOD.BDC2.5 TCR transgenic mice to Yeti mice, which express a YFP reporter cassette under the control of the IFN-\u03B3 promoter 31. Tolerized BDC2.5.Thy1.1.Yeti T cells were transferred to recipient NOD mice and" . . . _:b414677047 . _:b414677153 . . . _:b414677536 . _:b414676594 . . _:b6102607 "2b, M = 0.32 \u00B1 0.16 \u03BCm2 min-1) 22,>>33<<,34. In contrast, the displacement of tolerized BDC2.5 T cells was significantly higher (M = 6.65 \u00B1 0.21 \u03BCm2 min-1, Fig." . _:b414677445 . . . _:b414677706 . . . _:b414677599 . . . . . _:b414677018 . _:b414676809 . _:b414676343 . _:b414677337 . . . . . . _:b414676940 . . . . . _:b414676674 . . . . . _:b414677472 . . . _:b414676428 . _:b414676535 . _:b414677743 . . _:b414676370 . _:b414676550 . . _:b414676749 . _:b414677600 . . . . . . . . _:b414677666 . . _:b414677844 . _:b414677275 . _:b414677847 . _:b414677072 . . _:b6102573 "Programmed death-1 (PD-1) is an inhibitory molecule found on the surface of activated B and T cells and has been implicated in immune tolerance >>6<<. PD-1 (also called CD279) is a member of the CD28 and CTLA-4 immunoglobulin superfamily and interacts with two B7 family ligands, PD-L1 (also called CD274) and PD-L2 (also called CD273) 4." . _:b414677774 . _:b414676338 . _:b414677393 . . . . _:b414676459 . _:b414677133 . _:b6102638 "Several other reports illustrated that during the induction of T cell tolerance both transient and stable DC interactions can occur 20,>>23<<. During the process of T cell activation the duration of T cell-DC contacts is highly variable in vivo, ranging from minutes to several hours 39. Early reports suggested that initial interactions during the first phase of T cell" . . . . . _:b414677331 . . _:b414677281 . _:b6102612 "PD-1\u2013mediated control of immune responses depends on interactions between PD-1 on T cells and PD-L1 ligand in tissues 10,>>11<<. Thus, we sought to determine if the effects of PD-1-PD-L1 blockade had similar effects in the autoimmune target tissue, the pancreatic islets, as was the case in antigen draining PLN." . . . . _:b414677642 . . . _:b414677801 . _:b6102643 . . . . _:b6102644 . . . _:b414677248 . . _:b414677520 . _:b414677754 . . . _:b6102621 . _:b414676648 . _:b414676642 . _:b414677576 . . _:b6102596 . . . _:b414677624 . _:b414677313 . _:b414676383 . . . _:b414676617 . _:b6102636 . _:b414677025 . _:b414677312 . . _:b414677863 . . . . _:b414677207 . _:b414677223 . . _:b414677151 . _:b6102591 . . _:b414677447 . . . . . _:b6102567 . _:b414676827 . . . . . . . _:b414676760 . _:b414676575 . _:b414676485 "5"^^ . _:b414676484 "5"^^ . _:b414676487 "5"^^ . _:b414676486 "5"^^ . _:b414677029 . . . _:b414676714 . _:b414676481 "5"^^ . _:b414676480 "5"^^ . _:b414677125 . _:b414676483 "5"^^ . . . _:b414676856 . _:b414676482 "5"^^ . _:b414677673 . . _:b414676493 "5"^^ . _:b414677159 . _:b414677535 . _:b414676492 "5"^^ . _:b414676495 "5"^^ . . . . _:b414676707 . _:b414676494 "5"^^ . _:b414676489 "5"^^ . _:b414676488 "5"^^ . _:b6102623 "Nussenzweig (The Rockefeller University, New York, NY) >>32<< mice were backcrossed for more than 10 generations to NOD." . _:b414676491 "5"^^ . _:b414677851 . _:b414676490 "5"^^ . . _:b414676528 . _:b414676501 "5"^^ . _:b414676859 . _:b414676500 "5"^^ . _:b414677451 . _:b414676503 "5"^^ . _:b414676502 "5"^^ . _:b414677411 . _:b414677823 . . _:b414676497 "5"^^ . . _:b414676496 "5"^^ . _:b414677781 . . _:b414676499 "5"^^ . _:b414676442 . _:b414677323 . _:b414676641 . . _:b414676498 "5"^^ . _:b414676509 "4"^^ . . . _:b414676508 "4"^^ . _:b6102595 . _:b414676511 "4"^^ . _:b414677263 . . _:b414676510 "4"^^ . . . _:b414676680 . _:b414676505 "5"^^ . . _:b414676504 "5"^^ . . . _:b414676342 . . _:b414677530 . _:b414676507 "5"^^ . . _:b414677893 . _:b414677400 . _:b414676506 "5"^^ . _:b414676771 . _:b6102586 "Although both PD-1 and CTLA-4 interactions were critical for the induction of tolerance, the long term maintenance of the anergic state depended on PD-1-PD-L1 interactions, but not CTLA-4 interactions within the inflamed tissue >>10<<. These results implied that a cell-intrinsic mechanism maintains tolerance in the setting of continual exposure to autoantigen." . _:b414676754 . _:b414676517 "4"^^ . _:b414676353 . _:b414676526 . . . . _:b414677056 . _:b414676516 "4"^^ . . _:b414677409 . . _:b414676519 "4"^^ . _:b414677759 . _:b414676740 . _:b6102571 . . _:b414676518 "4"^^ . . _:b414676513 "4"^^ . _:b414676512 "4"^^ . . _:b414677810 . . _:b414676515 "4"^^ . . . . _:b414676514 "4"^^ . _:b414677116 . _:b414676463 . _:b414677396 . _:b414676525 "4"^^ . _:b414676524 "4"^^ . . _:b414677160 . _:b414676527 "4"^^ . _:b414676526 "4"^^ . _:b6102594 "TCR ligation results in \u2018stop signals\u2019 that decrease T cell motility and are required for stable T cell-DC conjugate formation and development of the immunological synapse 21,>>26<<. Prolonged T cell-DC interactions are critical for full T cell activation, proliferation and cytokine production 27-29. However, T cell movement and velocity during the long term maintenance of tolerance has not been well described." . _:b414676521 "4"^^ . . _:b414676406 . _:b414676520 "4"^^ . . _:b6102615 . _:b414676523 "4"^^ . . _:b414676522 "4"^^ . _:b414676533 "4"^^ . _:b414676532 "4"^^ . _:b6102654 "Mutation of the ITIM motif had little effect on signaling, while ITSM mutations abrogated the ability of PD-1 to limit T cell population expansion >>43<<. This suggests that PD-1 and CTLA-4 use different structural motifs to bind and recruit phosphatases for signal blockade. Future work is necessary to determine the precise biochemical relationship between these two potent negative" . . _:b414677074 . _:b414676535 "4"^^ . _:b414676534 "4"^^ . _:b414676529 "4"^^ . . _:b414676528 "4"^^ . _:b414677829 . _:b414676531 "4"^^ . . _:b414676530 "4"^^ . _:b414676320 . _:b414676541 "4"^^ . . _:b414676540 "4"^^ . . _:b414676404 . _:b414676543 "4"^^ . . _:b414676542 "4"^^ . _:b414676537 "4"^^ . _:b414676536 "4"^^ . . _:b414676539 "4"^^ . _:b414677694 . . _:b414676538 "4"^^ . _:b6102618 . _:b414676549 "4"^^ . _:b414676568 . . _:b414676548 "4"^^ . . _:b414676551 "4"^^ . _:b414677435 . _:b414676550 "4"^^ . . _:b414676545 "4"^^ . _:b414677175 . _:b414677867 . _:b414676544 "4"^^ . . _:b6102600 . _:b414676547 "4"^^ . . _:b6102579 "Similarly, blocking PD-1-PD-L1 interactions accelerates spontaneous autoimmune diabetes >>12<< and reverses immune tolerance 10,11." . _:b414676546 "4"^^ . _:b414677242 . _:b414676557 "4"^^ . _:b414676329 . . _:b414676556 "4"^^ . _:b414676666 . _:b414676682 . _:b414676559 "4"^^ . . _:b414677462 . . _:b414676558 "4"^^ . _:b414676498 . . . _:b414676553 "4"^^ . _:b414676829 . _:b414676552 "4"^^ . _:b414677388 . _:b414676555 "4"^^ . _:b414676347 . . _:b414676554 "4"^^ . . . _:b414676565 "4"^^ . . _:b414676747 . _:b414676564 "4"^^ . . _:b414676567 "4"^^ . _:b414676566 "4"^^ . _:b414677838 . . _:b414676561 "4"^^ . . _:b414676560 "4"^^ . _:b414677500 . . _:b414677266 . _:b414676563 "4"^^ . _:b414676562 "4"^^ . _:b414676772 . _:b414676573 "4"^^ . _:b414676572 "4"^^ . _:b414676575 "4"^^ . _:b414676574 "4"^^ . _:b414676967 . _:b414676854 . _:b414677208 . _:b414676569 "4"^^ . _:b414677422 . _:b414676568 "4"^^ . . . _:b414677644 . _:b414676571 "4"^^ . _:b414676570 "4"^^ . . _:b414676581 "4"^^ . . . _:b414677276 . _:b414676598 . _:b414676580 "4"^^ . _:b414676710 . _:b414677581 . _:b414676333 . _:b414676898 . _:b414676583 "4"^^ . . _:b414677016 . _:b414676582 "4"^^ . _:b414677070 . . _:b414676994 . _:b414676577 "4"^^ . . . _:b414677585 . _:b414676364 . _:b414677657 . _:b414676576 "4"^^ . . _:b414676579 "4"^^ . . _:b414676578 "4"^^ . _:b414676784 . _:b414676589 "4"^^ . _:b414676616 . _:b414677591 . . _:b414676588 "4"^^ . _:b414677118 . _:b414676591 "4"^^ . . _:b414676590 "4"^^ . _:b414677510 . _:b414676585 "4"^^ . . _:b414676584 "4"^^ . . _:b414676587 "4"^^ . . . _:b414676586 "4"^^ . _:b6102621 "methods" . _:b414676973 . _:b414676597 "4"^^ . . _:b414676596 "4"^^ . . _:b414676599 "4"^^ . . _:b414676649 . _:b414676598 "4"^^ . _:b414676593 "4"^^ . _:b414676592 "4"^^ . _:b414677127 . _:b414676595 "4"^^ . _:b414677446 . . _:b414676594 "4"^^ . _:b414676783 . _:b414676605 "4"^^ . _:b414676489 . . _:b414676604 "4"^^ . . _:b414677080 . _:b414676600 . _:b414677001 . _:b414676607 "4"^^ . _:b414676606 "4"^^ . . _:b414676825 . . _:b414676601 "4"^^ . _:b414677318 . . _:b414676600 "4"^^ . _:b414676603 "4"^^ . _:b414676602 "4"^^ . _:b414676613 "4"^^ . _:b414677689 . . _:b414677038 . _:b414676612 "4"^^ . _:b414676615 "4"^^ . _:b6102612 . . _:b414676614 "4"^^ . _:b414676609 "4"^^ . _:b414676551 . _:b414676608 "4"^^ . . . _:b414676611 "4"^^ . _:b414677354 . _:b414676610 "4"^^ . _:b414676621 "4"^^ . _:b414676620 "4"^^ . _:b414677234 . _:b414676400 . _:b414676623 "4"^^ . _:b414676622 "4"^^ . _:b414676617 "4"^^ . _:b414676616 "4"^^ . _:b414676359 . _:b414677653 . _:b414676619 "4"^^ . . _:b414676618 "4"^^ . "10.1038%2Fni.1790" . _:b414676629 "4"^^ . . . _:b414676628 "4"^^ . _:b414676631 "3"^^ . _:b414676468 . _:b414676955 . . _:b414676937 . . _:b414676630 "4"^^ . _:b414676481 . _:b414677093 . _:b414677053 . _:b414676625 "4"^^ . _:b414676430 . . _:b414676624 "4"^^ . _:b414676911 . . _:b414676627 "4"^^ . _:b414676626 "4"^^ . . . _:b414676637 "3"^^ . . _:b414676636 "3"^^ . . . _:b414676639 "3"^^ . _:b414676862 . _:b414676638 "3"^^ . . _:b414677643 . _:b414676633 "3"^^ . _:b414676632 "3"^^ . _:b414676635 "3"^^ . . _:b414676634 "3"^^ . _:b414676743 . . . _:b414676645 "3"^^ . . _:b414676644 "3"^^ . . . . . _:b414677765 . . _:b414676647 "3"^^ . _:b414676646 "3"^^ . _:b414677236 . _:b414676641 "3"^^ . _:b414676640 "3"^^ . _:b414677143 . _:b414676643 "3"^^ . . . _:b414676340 . _:b414676642 "3"^^ . _:b414677776 . _:b414677830 . _:b414676653 "3"^^ . _:b414676314 . _:b414677357 . _:b414676652 "3"^^ . . . _:b414677317 . _:b414676655 "3"^^ . _:b414676654 "3"^^ . . _:b414676649 "3"^^ . . _:b414676648 "3"^^ . _:b414676651 "3"^^ . _:b414676482 . _:b6102624 . _:b414676650 "3"^^ . _:b414677468 . . _:b414676661 "3"^^ . _:b414676966 . _:b414676660 "3"^^ . . _:b414677385 . _:b414676663 "3"^^ . _:b414676654 . _:b414676662 "3"^^ . _:b414676401 . _:b414676657 "3"^^ . _:b414676656 "3"^^ . . _:b414676924 . _:b414676659 "3"^^ . . _:b414676658 "3"^^ . _:b414676669 "3"^^ . . _:b414677848 . _:b414676668 "3"^^ . . _:b414676439 . _:b414676671 "3"^^ . _:b414676916 . . _:b414677372 . . _:b414676670 "3"^^ . _:b414677315 . _:b414677253 . . _:b414677328 . . _:b414677649 . _:b414676665 "3"^^ . _:b414676664 "3"^^ . . _:b414676667 "3"^^ . . . _:b414676666 "3"^^ . _:b414676300 . . . _:b414676677 "3"^^ . . _:b414676676 "3"^^ . _:b414676679 "3"^^ . _:b414676678 "3"^^ . _:b6102587 . _:b414677291 . _:b414676673 "3"^^ . . _:b414676672 "3"^^ . _:b414677885 . . _:b414676675 "3"^^ . _:b414676355 . _:b414676674 "3"^^ . _:b414676685 "3"^^ . . . _:b414676684 "3"^^ . _:b414676414 . _:b414676687 "3"^^ . . . . _:b414677002 . _:b414676686 "3"^^ . . _:b414676681 "3"^^ . _:b6102611 "PD-1\u2013mediated control of immune responses depends on interactions between PD-1 on T cells and PD-L1 ligand in tissues >>10<<,11. Thus, we sought to determine if the effects of PD-1-PD-L1 blockade had similar effects in the autoimmune target tissue, the pancreatic islets, as was the case in antigen draining PLN." . _:b414676680 "3"^^ . . _:b414676602 . _:b414676683 "3"^^ . . _:b414676492 . _:b414676682 "3"^^ . _:b414677101 . _:b414676693 "3"^^ . _:b414676692 "3"^^ . _:b414676695 "3"^^ . . _:b414677633 . _:b414676694 "3"^^ . . _:b414677434 . _:b414676689 "3"^^ . . _:b414676688 "3"^^ . . _:b414677246 . _:b414676691 "3"^^ . . _:b414676690 "3"^^ . _:b414676373 . _:b414676701 "3"^^ . _:b414676971 . _:b414676700 "3"^^ . . . . _:b414676703 "3"^^ . . _:b414676781 . _:b414676702 "3"^^ . . . _:b6102644 "In this study, Erk phosphorylation occurred early after stable T cell-DC conjugates were formed, and IFN-\u03B3 production increased with longer T cell-DC interactions >>41<<. These interactions required TCR engagement of peptide-MHCII complexes, as MHCII blockade in vivo terminated stable contacts, increased T cell motility, decreased T cell proliferation and prevented IFN-\u03B3 production. The second phase" . . _:b414677645 . _:b414676697 "3"^^ . _:b6102578 . _:b414676696 "3"^^ . _:b414676411 . _:b6102608 "2b, M = 0.32 \u00B1 0.16 \u03BCm2 min-1) 22,33,>>34<<. In contrast, the displacement of tolerized BDC2.5 T cells was significantly higher (M = 6.65 \u00B1 0.21 \u03BCm2 min-1, Fig." . _:b414676699 "3"^^ . _:b414676698 "3"^^ . _:b414676709 "3"^^ . . . . _:b414676708 "3"^^ . . _:b6102581 . _:b414676711 "3"^^ . _:b414676710 "3"^^ . _:b414677177 . _:b414677805 . . _:b414676705 "3"^^ . . _:b414677802 . _:b414676704 "3"^^ . _:b414676707 "3"^^ . _:b414676706 "3"^^ . _:b414676816 . _:b414676717 "3"^^ . . . _:b414676716 "3"^^ . . _:b414676719 "3"^^ . . _:b414676718 "3"^^ . _:b414677475 . _:b414676713 "3"^^ . _:b414676712 "3"^^ . . _:b414676715 "3"^^ . _:b414676866 . _:b414676714 "3"^^ . . _:b414676725 "3"^^ . _:b414677258 . _:b414676493 . _:b414676387 . _:b414677491 . _:b414676724 "3"^^ . _:b414676377 . _:b414676727 "3"^^ . . _:b414676726 "3"^^ . _:b414676721 "3"^^ . _:b414676720 "3"^^ . . _:b414676723 "3"^^ . _:b414676672 . _:b414677407 . _:b414676722 "3"^^ . . . _:b414676733 "3"^^ . _:b414677022 . . . . _:b414676732 "3"^^ . _:b414677860 . _:b414676735 "3"^^ . . . _:b414676734 "3"^^ . . _:b414676729 "3"^^ . . _:b414677100 . _:b414676728 "3"^^ . _:b414676621 . _:b414677326 . _:b414677006 . _:b414677579 . _:b414676731 "3"^^ . _:b414676622 . _:b414676730 "3"^^ . . _:b414677031 . _:b414676741 "3"^^ . _:b414677551 . _:b414677119 . _:b414676797 . _:b414677699 . _:b414676740 "3"^^ . _:b414676464 . _:b414676743 "3"^^ . . . _:b414676742 "3"^^ . . _:b414676737 "3"^^ . _:b414677498 . _:b414676736 "3"^^ . _:b414676739 "3"^^ . _:b414676727 . . . _:b414677695 . _:b414676738 "3"^^ . _:b6102584 "However, the effects of PD-1 engagement during T cell activation are unclear as in vitro models do not adequately demonstrate the inhibitory activity of PD-1 >>17<<. In vivo studies of PD-1\u2013mediated inhibition have been limited to global effects on immunity with little direct evidence that PD-1 engagement directly controls T cell signaling." . _:b414676749 "3"^^ . . . _:b414676779 . _:b414676748 "3"^^ . _:b414677045 . _:b414676396 . _:b414676751 "3"^^ . _:b414676750 "3"^^ . . _:b414676745 "3"^^ . . _:b414677423 . . _:b414676744 "3"^^ . _:b414676747 "3"^^ . _:b414676475 . _:b414676746 "3"^^ . . . _:b414676757 "3"^^ . _:b414676325 . _:b414677185 . _:b414676756 "3"^^ . _:b414676785 . _:b414676759 "3"^^ . _:b414676758 "3"^^ . . . _:b414676753 "3"^^ . _:b414676793 . _:b414676752 "3"^^ . . _:b414676755 "3"^^ . . _:b414676510 . _:b414676754 "3"^^ . _:b414676765 "3"^^ . . _:b414676764 "3"^^ . _:b414676334 . _:b414676767 "3"^^ . _:b414676766 "3"^^ . . _:b414676302 . _:b414676761 "3"^^ . _:b414677891 . _:b414676760 "3"^^ . _:b414676763 "3"^^ . _:b414676762 "3"^^ . . _:b414677301 . _:b414676773 "3"^^ . _:b414676772 "3"^^ . _:b414676775 "3"^^ . . _:b414677132 . _:b414676774 "3"^^ . . _:b414676769 "3"^^ . _:b414676378 . _:b414676768 "3"^^ . . _:b414677779 . . _:b414676608 . _:b414676771 "3"^^ . . _:b414677268 . _:b414676758 . _:b414676868 . _:b414676770 "3"^^ . . _:b414676781 "3"^^ . _:b414676780 "3"^^ . _:b414676842 . _:b414676787 . _:b414677770 . _:b414676783 "3"^^ . . _:b414677209 . _:b414676782 "3"^^ . _:b414676874 . _:b414677436 . _:b414676777 "3"^^ . . . _:b414676776 "3"^^ . _:b414676779 "3"^^ . . _:b414676778 "3"^^ . _:b414676877 . _:b414676789 "3"^^ . _:b414676416 . . _:b414676788 "3"^^ . . _:b414677050 . _:b414676791 "3"^^ . _:b414676790 "3"^^ . . _:b414676785 "3"^^ . _:b414676784 "3"^^ . _:b414676787 "3"^^ . . _:b414676786 "3"^^ . _:b414676565 . _:b414676797 "3"^^ . _:b414676796 "3"^^ . . . _:b414677320 . _:b414676799 "3"^^ . . . _:b414676798 "3"^^ . _:b414677350 . _:b414676793 "3"^^ . _:b414676983 . _:b414676792 "3"^^ . . _:b414676795 "3"^^ . . _:b414676339 . _:b414676794 "3"^^ . _:b414676756 . _:b414676805 "3"^^ . . . _:b414676566 . _:b414676804 "3"^^ . . _:b414676807 "3"^^ . _:b414677412 . . _:b414676638 . _:b414677492 . _:b414676806 "3"^^ . _:b414677794 . _:b414676801 "3"^^ . _:b414676800 "3"^^ . _:b414676753 . _:b414676803 "3"^^ . _:b414676802 "3"^^ . . _:b414676813 "3"^^ . _:b414677238 . _:b414676812 "3"^^ . . _:b414676815 "3"^^ . _:b414676934 . _:b414677545 . _:b414676814 "3"^^ . . _:b414676809 "3"^^ . . _:b414676808 "3"^^ . _:b414676811 "3"^^ . _:b414676907 . _:b414676810 "3"^^ . _:b414677883 . _:b414676905 . . _:b414676857 . _:b414676821 "3"^^ . _:b414677519 . _:b414676820 "3"^^ . _:b414676823 "3"^^ . . _:b414677076 . _:b414676822 "3"^^ . _:b414677174 . . . _:b414676817 "3"^^ . _:b414677369 . _:b414676816 "3"^^ . _:b414677375 . _:b414676819 "3"^^ . . _:b414676818 "3"^^ . . _:b414676829 "3"^^ . . _:b6102618 . _:b414676828 "3"^^ . _:b414677659 . _:b414676831 "3"^^ . _:b414676830 "3"^^ . . _:b414677725 . _:b414676825 "3"^^ . _:b414676527 . _:b6102652 "Unlike PD-1, CTLA-4 can also interact with the phosphatase PP2a >>15<<. Another difference between these two inhibitory receptors is the structural motif used to bind phosphatases." . _:b414677303 . _:b414676824 "3"^^ . . _:b414676827 "3"^^ . _:b6102568 "afcsid=A000706) is a well established negative regulator of T cell function >>1<<. CTLA-4 is rapidly expressed on the surface of T cells following activation and is highly upregulated by engagement of the co-stimulatory molecule CD28 1." . _:b414677878 . _:b414677195 . _:b414676826 "3"^^ . _:b414677008 . _:b414677062 . _:b414676515 . . . _:b414676837 "3"^^ . _:b414676836 "3"^^ . _:b414676839 "3"^^ . . _:b414676838 "3"^^ . _:b414677408 . _:b414676833 "3"^^ . _:b414677756 . _:b414676867 . _:b414676832 "3"^^ . . _:b414677319 . _:b414676835 "3"^^ . _:b414676834 "3"^^ . . . _:b414676845 "3"^^ . _:b414676625 . . _:b414676844 "3"^^ . _:b414676847 "3"^^ . _:b414676516 . . _:b414676846 "3"^^ . . _:b414676841 "3"^^ . _:b414676840 "3"^^ . . _:b414677796 . _:b414676315 . . _:b414676843 "3"^^ . . _:b414676423 . _:b414676842 "3"^^ . _:b414676853 "3"^^ . _:b414676852 "3"^^ . _:b414676837 . _:b414676855 "3"^^ . . _:b414676854 "3"^^ . _:b414676668 . _:b414676849 "3"^^ . _:b414677295 . _:b414676848 "3"^^ . _:b414677506 . _:b414676851 "3"^^ . . _:b414676850 "3"^^ . . . _:b414676861 "3"^^ . _:b414676721 . _:b414676860 "3"^^ . _:b414676863 "3"^^ . . _:b414677698 . . _:b414676630 . _:b414676862 "3"^^ . . _:b414677170 . _:b414677094 . _:b414676857 "3"^^ . _:b414676382 . . _:b414676856 "3"^^ . _:b414676848 . _:b414676859 "3"^^ . _:b414677800 . _:b414676858 "3"^^ . _:b414676869 "3"^^ . . _:b414677439 . _:b414676745 . _:b414676868 "3"^^ . _:b414677610 . _:b414676871 "3"^^ . _:b414676870 "3"^^ . _:b414676959 . _:b414676865 "3"^^ . . _:b414676864 "3"^^ . _:b414676867 "3"^^ . _:b414677244 . . _:b414676866 "3"^^ . . _:b414676877 "3"^^ . . . _:b414676876 "3"^^ . . _:b414676775 . _:b414676879 "3"^^ . _:b414677783 . . _:b414677043 . . . _:b414676878 "3"^^ . . _:b414677213 . _:b414676873 "3"^^ . _:b6102572 "Mice deficient for CTLA-4 develop lymphoproliferative disease and die within 3-4 weeks of birth >>5<<, adding further evidence for the critical role of CTLA-4 in controlling T cell responses and immune homeostasis." . _:b414676872 "3"^^ . _:b414676875 "3"^^ . . _:b414676874 "3"^^ . _:b414677252 . _:b414676885 "3"^^ . _:b414676348 . _:b414677556 . _:b414676884 "3"^^ . . . . _:b414676887 "3"^^ . . . _:b414676886 "3"^^ . _:b414676881 "3"^^ . _:b414676880 "3"^^ . _:b414676883 "3"^^ . . _:b414676882 "3"^^ . _:b414676893 "2"^^ . . _:b414676853 . _:b414676892 "2"^^ . . _:b414677427 . . _:b414676895 "2"^^ . _:b414677204 . _:b414676894 "2"^^ . _:b414676889 "3"^^ . _:b414676888 "3"^^ . _:b414676978 . _:b414676891 "3"^^ . _:b414676961 . _:b414676890 "3"^^ . _:b414676901 "2"^^ . . _:b414676900 "2"^^ . _:b414676903 "2"^^ . . _:b414676902 "2"^^ . _:b414677845 . . _:b414676897 "2"^^ . _:b414676432 . _:b414676620 . _:b414676896 "2"^^ . . . _:b414676899 "2"^^ . . . _:b414677479 . . . _:b414676898 "2"^^ . . _:b414676909 "2"^^ . _:b414676968 . _:b414676832 . _:b414677243 . _:b414676908 "2"^^ . _:b414676911 "2"^^ . _:b414677547 . _:b414676910 "2"^^ . _:b414677548 . _:b414676905 "2"^^ . _:b414676367 . _:b414676521 . _:b414676904 "2"^^ . . _:b414677011 . _:b414676907 "2"^^ . _:b414677734 . _:b414676906 "2"^^ . . . _:b414676917 "2"^^ . . _:b414676916 "2"^^ . . . _:b414676919 "2"^^ . . _:b414676918 "2"^^ . . _:b414676913 "2"^^ . . . _:b414676912 "2"^^ . _:b414676915 "2"^^ . _:b414676975 . . _:b414676914 "2"^^ . _:b414677738 . _:b414676925 "2"^^ . . _:b414676924 "2"^^ . _:b414676927 "2"^^ . _:b414676926 "2"^^ . . _:b414676921 "2"^^ . . _:b414677670 . _:b414676920 "2"^^ . _:b414677843 . _:b414677111 . _:b414676923 "2"^^ . . _:b414677628 . _:b414676922 "2"^^ . . _:b414676933 "2"^^ . _:b414676932 "2"^^ . _:b414677019 . _:b6102595 . _:b414676935 "2"^^ . _:b414676934 "2"^^ . _:b414676512 . _:b414676421 . _:b414676929 "2"^^ . . . _:b414677493 . _:b414677413 . _:b414676928 "2"^^ . _:b414677424 . _:b414676579 . . _:b414676931 "2"^^ . _:b414676930 "2"^^ . . _:b414676604 . _:b414676341 . _:b414676941 "2"^^ . . _:b414677377 . _:b6102631 "injections of 50 \u00D7 106 chemically treated antigen-coupled syngeneic splenocytes (p31 or SHAM control), as described previously >>10<<." . _:b414676940 "2"^^ . _:b414676943 "2"^^ . _:b414676942 "2"^^ . _:b414676937 "2"^^ . . . . _:b414677762 . _:b414676936 "2"^^ . . _:b414676939 "2"^^ . . _:b414676938 "2"^^ . _:b414676695 . _:b414676949 "2"^^ . _:b414677737 . _:b414676948 "2"^^ . . _:b414676951 "2"^^ . _:b414676501 . _:b414676950 "2"^^ . _:b414676945 "2"^^ . _:b414676944 "2"^^ . _:b414677226 . _:b414676947 "2"^^ . _:b6102614 . _:b414676946 "2"^^ . _:b414676957 "2"^^ . . _:b414676326 . _:b414676956 "2"^^ . _:b414676959 "2"^^ . _:b414677003 . _:b414677085 . . _:b414676958 "2"^^ . . _:b414676953 "2"^^ . _:b414676952 "2"^^ . _:b414677007 . _:b414676879 . _:b414676955 "2"^^ . _:b414676928 . _:b414676954 "2"^^ . . _:b414676965 "2"^^ . . _:b414677109 . _:b414676964 "2"^^ . _:b414677615 . _:b414676967 "2"^^ . . _:b414677112 . . . _:b414676966 "2"^^ . . _:b414676961 "2"^^ . _:b414676960 "2"^^ . _:b6102598 "We previously identified a critical role for PD-1 but not CTLA-4 in the maintenance of tolerance induced by injection of insulin-coupled fixed splenocytes >>10<<. Herein, we adapted this model using islet antigen-specific BDC2.5 TCR transgenic T cells to define the role of PD-1 and CTLA-4 in the maintenance of peripheral tolerance." . _:b414677448 . _:b414676963 "2"^^ . . _:b414676962 "2"^^ . . _:b414676629 . _:b414677341 . _:b414676973 "2"^^ . _:b414676539 . _:b414676972 "2"^^ . _:b414676975 "2"^^ . _:b414676750 . _:b414676974 "2"^^ . _:b414676969 "2"^^ . . _:b414676517 . _:b414676968 "2"^^ . _:b414677568 . _:b414676971 "2"^^ . _:b414676970 "2"^^ . _:b414676718 . _:b414676981 "2"^^ . _:b414677305 . _:b414676980 "2"^^ . . _:b414676851 . _:b414676983 "2"^^ . . _:b414676982 "2"^^ . _:b414676977 "2"^^ . _:b414677099 . _:b414676701 . _:b414676976 "2"^^ . . . . _:b414676979 "2"^^ . . . _:b414676978 "2"^^ . . . _:b414676989 "2"^^ . . _:b414677077 . . _:b414677384 . _:b414676988 "2"^^ . . _:b414676901 . . _:b414676991 "2"^^ . _:b414676990 "2"^^ . _:b414676985 "2"^^ . . . _:b414676984 "2"^^ . . . _:b414677890 . . _:b414676323 . . . . _:b414676987 "2"^^ . _:b414677828 . _:b414676537 . . _:b414676986 "2"^^ . _:b414677782 . . _:b414676297 . . . . . _:b414677139 . _:b414677128 . . _:b414676893 . _:b414677604 . _:b414677508 . . . . _:b414676658 . _:b414677442 . . _:b414677639 . . . _:b414676590 . _:b414676932 . . _:b414676292 . . _:b414676717 . _:b414676635 . . _:b414677636 . _:b414677477 . . . . _:b414676900 . . _:b414677046 . _:b414677717 . _:b414676927 . _:b6102606 "2b, M = 0.32 \u00B1 0.16 \u03BCm2 min-1) >>22<<,33,34. In contrast, the displacement of tolerized BDC2.5 T cells was significantly higher (M = 6.65 \u00B1 0.21 \u03BCm2 min-1, Fig." . _:b414677814 . . . _:b414677744 . . . _:b414677769 . . . . . _:b6102661 "One major difference is the previous reports tracked the migration of na\u00EFve T cells during primary stimulation 44,>>45<< whereas the present studies focused on anergic T cells during the re-activation phase." . . . _:b414676977 . _:b6102570 "CTLA-4 ligation antagonizes early T cell activation leading to decreased interleukin 2 (IL-2) production, inhibition of cell cycle progression and modulation of TCR signaling >>2<<,3. CTLA-4 and CD28 shares the ligands B7-1 (also called CD80) and B7-2 (also called CD86) 4. Mice deficient for CTLA-4 develop lymphoproliferative disease and die within 3-4 weeks of birth 5, adding further evidence for the critical role" . _:b414677137 . _:b414676878 . _:b414676945 . _:b414676802 . _:b414677692 . . . _:b414677789 . . . . . _:b414676686 . . . . _:b414677834 . _:b414677739 . _:b414677211 . . _:b414676914 . . . _:b414677339 . _:b414677163 . _:b414676388 . . _:b414676354 . . _:b414677054 . _:b414676637 . . _:b414676826 . . _:b414676374 . _:b414676443 . _:b414677555 . _:b414677831 . _:b414677460 . _:b414677130 . . _:b414677509 "2"^^ . _:b414677404 . . _:b414677508 "2"^^ . . _:b414677189 . _:b414677036 . _:b414677511 "2"^^ . _:b414677186 . _:b414677346 . . _:b414677510 "2"^^ . . _:b414677505 "2"^^ . _:b414677504 "2"^^ . _:b414677507 "2"^^ . . _:b414677714 . . _:b414677040 . _:b414677506 "2"^^ . _:b414677517 "2"^^ . _:b414677516 "2"^^ . _:b414677487 . _:b414676766 . _:b414677519 "2"^^ . _:b414677518 "2"^^ . _:b414677652 . . _:b414677513 "2"^^ . . _:b414677512 "2"^^ . _:b414677515 "2"^^ . _:b414677855 . _:b414677514 "2"^^ . _:b414676824 . _:b414676357 . _:b414677525 "2"^^ . _:b414677282 . _:b414676371 . . . _:b414677524 "2"^^ . _:b414677527 "2"^^ . _:b414677526 "2"^^ . _:b6102637 "Several other reports illustrated that during the induction of T cell tolerance both transient and stable DC interactions can occur >>20<<,23. During the process of T cell activation the duration of T cell-DC contacts is highly variable in vivo, ranging from minutes to several hours 39. Early reports suggested that initial interactions during the first phase of T cell" . . _:b414677521 "2"^^ . . _:b414677520 "2"^^ . _:b414676741 . _:b414676883 . _:b414677523 "2"^^ . _:b6102584 . _:b414676740 . _:b414677528 . _:b414677522 "2"^^ . _:b414676743 . _:b414677533 "2"^^ . _:b414676742 . . _:b414677532 "2"^^ . _:b414676737 . . _:b414677310 . _:b414676613 . _:b414677535 "2"^^ . _:b414676736 . . _:b414677534 "2"^^ . _:b414677786 . _:b414676739 . . _:b414676895 . _:b414677529 "2"^^ . _:b414676738 . _:b414677528 "2"^^ . _:b414676749 . _:b414676691 . _:b414677531 "2"^^ . _:b414676748 . _:b414677530 "2"^^ . _:b414676751 . . _:b414677541 "2"^^ . _:b414676750 . _:b414677540 "2"^^ . _:b414676745 . _:b414677543 "2"^^ . _:b414676744 . _:b414677757 . . _:b414677542 "2"^^ . _:b414676747 . _:b414677210 . _:b414677457 . _:b414677537 "2"^^ . _:b414676746 . . _:b414677536 "2"^^ . _:b414676757 . . _:b414677539 "2"^^ . _:b414676756 . . _:b414676570 . _:b414677538 "2"^^ . _:b414676759 . _:b414677549 "2"^^ . _:b414676758 . _:b414676884 . _:b414677548 "2"^^ . _:b414676753 . . _:b414676559 . _:b414677551 "2"^^ . _:b414676752 . _:b414677550 "2"^^ . _:b414676755 . _:b414676803 . _:b414677545 "2"^^ . _:b414676754 . . _:b414677142 . _:b414677544 "2"^^ . _:b414676765 . _:b414677804 . _:b414677547 "2"^^ . _:b414676764 . . . _:b414676445 . _:b414677546 "2"^^ . _:b414677176 . _:b414676767 . _:b414677557 "2"^^ . _:b414676766 . . _:b414677556 "2"^^ . _:b414676761 . _:b414677619 . . . _:b414677559 "2"^^ . _:b414676760 . _:b414677558 "2"^^ . _:b414676763 . . _:b414676746 . _:b414676845 . _:b414677553 "2"^^ . _:b414676762 . . _:b414677552 "2"^^ . _:b414676773 . _:b414677555 "2"^^ . _:b414676772 . . _:b414677554 "2"^^ . _:b414677832 . _:b414676775 . _:b6102582 "PD-L1 may act passively by competing directly with CD28 for B7-1 binding >>13<<. In addition, PD-1 may directly recruit phosphatases such as SHP-1, SHP-2 and PP2A, which interfere with TCR signaling 4,14-16." . _:b414677565 "2"^^ . _:b414676774 . . _:b414677564 "2"^^ . _:b414676769 . . . _:b414677567 "2"^^ . _:b414676768 . _:b414676660 . _:b414677566 "2"^^ . _:b414676771 . _:b414677561 "2"^^ . _:b414677748 . _:b414676770 . . _:b414677560 "2"^^ . _:b414677676 . _:b414676781 . _:b414677110 . _:b414677563 "2"^^ . _:b414676780 . _:b414677203 . _:b414677562 "2"^^ . _:b414676783 . . _:b414677573 "2"^^ . _:b414676782 . _:b414677572 "2"^^ . _:b414677167 . _:b414676777 . . . . _:b414677575 "2"^^ . _:b414676634 . _:b414676776 . _:b6102653 "CTLA-4 interacts through the immunoreceptor tyrosine-based inhibitory motifs (ITIM) while PD-1 contains an additional motif, the immunoreceptor tyrosine-based switch motif (ITSM) >>43<<. Mutation of the ITIM motif had little effect on signaling, while ITSM mutations abrogated the ability of PD-1 to limit T cell population expansion 43. This suggests that PD-1 and CTLA-4 use different structural motifs to bind and recruit" . . _:b414677574 "2"^^ . _:b414676779 . _:b414677256 . _:b414677569 "2"^^ . _:b414676778 . _:b414677568 "2"^^ . _:b414676789 . _:b414677538 . _:b414677376 . _:b414677571 "2"^^ . _:b414676788 . _:b414677570 "2"^^ . _:b414676791 . _:b414676317 . _:b414677581 "2"^^ . _:b414676790 . . _:b414676738 . _:b414677580 "2"^^ . _:b414676785 . . _:b414676508 . _:b414677583 "2"^^ . _:b414676784 . . . _:b414677187 . _:b414677178 . _:b414677582 "2"^^ . _:b414676787 . _:b414677589 . _:b414677392 . _:b414677577 "2"^^ . _:b414676786 . _:b414677617 . _:b414677576 "2"^^ . _:b414676797 . _:b414677579 "2"^^ . _:b414676796 . _:b6102588 "Several groups have described the highly dynamic movement of CD4+ and CD8+ T cells, as well as DCs during T cell priming and tolerance induction >>19<<-23. Na\u00EFve circulating T cells enter the LN through high endothelial venules and move on a network of stromal cells called fibroblastic reticular cells (FRCs), which define the potential location and migratory range of T cells 24. The FRC" . . . _:b414677578 "2"^^ . _:b414676799 . _:b414677882 . _:b414677589 "2"^^ . _:b414676798 . . _:b414676814 . _:b414677588 "2"^^ . _:b414676793 . _:b414676384 . . _:b414677591 "2"^^ . _:b414677812 . _:b414676792 . . _:b414677590 "2"^^ . _:b414676795 . _:b414677585 "2"^^ . _:b414676794 . _:b414677563 . _:b414676850 . _:b414676574 . _:b414677584 "2"^^ . . _:b414676805 . . . _:b414677587 "2"^^ . _:b414676804 . _:b414677820 . . _:b414676469 . _:b414677586 "2"^^ . _:b414677205 . _:b414676807 . . _:b414677597 "2"^^ . _:b414676806 . _:b414677596 "2"^^ . _:b414676801 . _:b414677599 "2"^^ . _:b414676800 . _:b414676840 . _:b414677598 "2"^^ . _:b414676803 . _:b414677593 "2"^^ . _:b414676802 . _:b6102654 . _:b414677775 . _:b414677233 . _:b414677813 . _:b414676708 . _:b414677592 "2"^^ . _:b414676813 . _:b414676413 . . _:b414677595 "2"^^ . _:b414676812 . _:b414677202 . _:b414677594 "2"^^ . _:b414676815 . _:b6102653 . . _:b414676599 . . _:b414677605 "2"^^ . _:b414677294 . _:b414676814 . _:b6102650 . . _:b414677604 "2"^^ . _:b414676809 . _:b414676397 . _:b414677607 "2"^^ . _:b414676808 . _:b414676585 . . _:b414677028 . _:b414677606 "2"^^ . _:b414676811 . . _:b414677616 . _:b414677601 "2"^^ . _:b414676810 . _:b414677534 . _:b414676303 . _:b414676477 . _:b414677600 "2"^^ . _:b414676821 . . _:b414676451 . _:b414677603 "2"^^ . _:b414676820 . _:b414676791 . _:b414677602 "2"^^ . _:b414676823 . _:b414677613 "2"^^ . _:b414676822 . _:b414677228 . . _:b414677612 "2"^^ . _:b414676817 . _:b414676547 . _:b414677615 "2"^^ . _:b414676816 . . _:b414677614 "2"^^ . _:b414676819 . _:b414677490 . _:b414676947 . _:b414677609 "2"^^ . _:b414676818 . _:b6102629 "Anti\u2013PD-1 (RMP1-14), anti\u2013PD-L1 (MIH5, MIH6), and anti\u2013PD-L2 (TY25) were made as described previously 7,>>10<<. Anti-CTLA-4 (UC4F10), and anti-CTLA-4 Fab fragments were made as described previously 1. Mice were injected intraperitoneally with 250 \u03BCg anti\u2013PD-L1, anti\u2013PD-L2, anti-B7-1, anti-PD-1, or anti-CTLA-4 as indicated." . _:b414677608 "2"^^ . _:b414676829 . _:b414677611 "2"^^ . _:b414676828 . . _:b414677610 "2"^^ . _:b414676831 . _:b6102618 . _:b414677621 "2"^^ . _:b6102647 "Recent reports suggested that B7-1 and PD-L1 interact directly with each other to negatively regulate T cells >>13<<. Thus far, however, in vivo data to support the functionality of this interaction have not been reported." . _:b414676830 . _:b414677620 "2"^^ . _:b414676825 . . . _:b414677623 "2"^^ . _:b414676824 . _:b6102617 . _:b414676757 . _:b414677622 "2"^^ . _:b414676827 . . _:b414677617 "2"^^ . _:b414676826 . _:b414677215 . _:b414677430 . _:b414676427 . _:b414677616 "2"^^ . _:b414676837 . . _:b414677619 "2"^^ . _:b414676836 . . . _:b414677618 "2"^^ . _:b414676839 . _:b414677543 . . _:b414677361 . _:b414677629 "2"^^ . _:b414676838 . _:b414677628 "2"^^ . _:b414676833 . _:b414677631 "2"^^ . _:b414676832 . . _:b414677000 . _:b414677630 "2"^^ . _:b414676835 . _:b414677625 "2"^^ . _:b414676834 . _:b414677624 "2"^^ . _:b414676845 . _:b414677627 "2"^^ . _:b414676844 . _:b414677454 . _:b414677626 "2"^^ . _:b414676847 . _:b414677265 . _:b414677637 "2"^^ . _:b414676846 . . . _:b414677636 "2"^^ . _:b414676841 . _:b414677639 "2"^^ . _:b414676840 . _:b414677638 "2"^^ . _:b414676843 . _:b414677833 . _:b414676385 . _:b414677633 "2"^^ . _:b414676842 . _:b414677632 "2"^^ . _:b414676853 . _:b414676864 . _:b414677635 "2"^^ . _:b414676852 . _:b414677335 . _:b414677632 . _:b414677634 "2"^^ . _:b414676855 . . _:b414677273 . _:b414676587 . _:b414677645 "2"^^ . _:b414676854 . _:b414677271 . . _:b414677066 . _:b414677644 "2"^^ . . _:b414676849 . . _:b414677647 "2"^^ . _:b414676848 . _:b414677602 . . _:b414677646 "2"^^ . _:b414676851 . _:b414676778 . _:b414677641 "2"^^ . _:b414676850 . _:b414677344 . _:b414677640 "2"^^ . _:b414676861 . . . _:b414677643 "2"^^ . _:b414676860 . _:b414677642 "2"^^ . _:b414676863 . _:b414676941 . _:b414677653 "2"^^ . _:b414676862 . _:b414676522 . _:b414677652 "2"^^ . _:b414676857 . _:b414677655 "2"^^ . _:b414676856 . _:b414677366 . _:b414677654 "2"^^ . _:b414676859 . _:b414677649 "2"^^ . _:b414676858 . _:b414677251 . _:b414677648 "2"^^ . _:b414676869 . . _:b414676419 . _:b414677651 "2"^^ . _:b414676868 . . _:b414677650 "2"^^ . _:b414676871 . _:b414677661 "2"^^ . _:b414676870 . . _:b414677660 "2"^^ . _:b414676865 . . . _:b414677663 "2"^^ . _:b414676864 . . . _:b414677662 "2"^^ . _:b414676867 . _:b414676769 . . _:b6102575 . _:b414677657 "2"^^ . _:b414676866 . _:b414677656 "2"^^ . _:b414676877 . . . _:b414677659 "2"^^ . _:b414676876 . _:b414677108 . _:b414677791 . . _:b414677198 . . _:b414677658 "2"^^ . _:b414676879 . _:b414677117 . _:b414677669 "2"^^ . _:b414676878 . _:b414677486 . _:b414676726 . _:b414677668 "2"^^ . _:b414676873 . _:b414677671 "2"^^ . _:b6102594 . _:b414676872 . . _:b414677078 . . _:b414677670 "2"^^ . _:b414676875 . _:b414677665 "2"^^ . _:b6102592 . _:b414676874 . . . _:b414677664 "2"^^ . _:b414676885 . _:b414677172 . . . _:b414677667 "2"^^ . . _:b414676884 . "PMC0" . . _:b414677666 "2"^^ . _:b414676887 . . _:b414677113 . _:b414677677 "2"^^ . _:b414676886 . _:b414677166 . _:b414677676 "2"^^ . _:b414676881 . . _:b414677679 "2"^^ . _:b414676880 . _:b414677141 . _:b414677678 "2"^^ . _:b414676883 . _:b414677673 "2"^^ . _:b414676882 . _:b414677854 . . _:b414677672 "2"^^ . _:b414677562 . _:b414676893 . _:b414677415 . _:b414677675 "2"^^ . _:b414676892 . . . _:b414677674 "2"^^ . _:b414676895 . _:b414677327 . . _:b414676652 . _:b414677685 "2"^^ . _:b414676894 . _:b414677502 . . _:b414677684 "2"^^ . _:b414676889 . _:b414677687 "2"^^ . _:b414676888 . _:b414676491 . _:b414677355 . _:b414677686 "2"^^ . _:b414676891 . _:b414677681 "2"^^ . _:b414676890 . . _:b414677680 "2"^^ . _:b414676901 . . _:b414677683 "2"^^ . _:b414676900 . _:b414677682 "2"^^ . _:b414676903 . _:b414677693 "2"^^ . _:b414676902 . _:b414676807 . _:b414677692 "2"^^ . _:b414676897 . . _:b414677788 . _:b414677489 . _:b414677695 "2"^^ . _:b414676896 . . . _:b414677694 "2"^^ . _:b414676899 . . . _:b414676965 . _:b414677689 "2"^^ . _:b414676898 . _:b414677688 "2"^^ . _:b414676909 . _:b414677749 . . _:b414677691 "2"^^ . _:b414676908 . _:b414677690 "2"^^ . _:b414676911 . _:b414677877 . _:b414677701 "2"^^ . _:b414676910 . . _:b414677700 "2"^^ . . . _:b414676905 . _:b414677703 "2"^^ . _:b414676904 . . _:b414677702 "2"^^ . _:b414676907 . _:b414677658 . _:b6102652 . . _:b414677697 "2"^^ . _:b414676906 . _:b414677461 . _:b414677696 "2"^^ . _:b414676917 . _:b414676823 . _:b414677699 "2"^^ . _:b414676916 . . _:b414677067 . _:b414677698 "2"^^ . . _:b414676919 . _:b414677815 . . . . _:b414677709 "2"^^ . _:b414676918 . _:b414677708 "2"^^ . _:b414676913 . _:b414677711 "2"^^ . _:b414676912 . . _:b414677710 "2"^^ . _:b414676915 . . _:b414677705 "2"^^ . _:b414676914 . _:b414676640 . _:b414676327 . _:b414677704 "2"^^ . . _:b414676925 . _:b414676418 . . _:b414677707 "2"^^ . _:b414676924 . . . _:b414677706 "2"^^ . _:b414677767 . _:b414676927 . _:b414677717 "2"^^ . _:b414676926 . _:b414677716 "2"^^ . _:b414676921 . _:b414677895 . . _:b414677719 "2"^^ . _:b414677063 . _:b414676920 . _:b414677718 "2"^^ . _:b414676923 . _:b414676819 . _:b414676444 . _:b414677713 "2"^^ . _:b414676922 . _:b414676943 . _:b414677712 "2"^^ . _:b414676933 . _:b414676321 . _:b414676446 . _:b414677715 "2"^^ . _:b414676932 . . _:b414677714 "2"^^ . _:b414676935 . _:b414677455 . _:b414676301 . _:b414677391 . . _:b414677725 "2"^^ . . _:b414676934 . . . _:b414677724 "2"^^ . _:b414676929 . . _:b414677727 "2"^^ . _:b414676928 . _:b414677042 . . _:b414677726 "2"^^ . _:b414676931 . . . _:b414677721 "2"^^ . _:b414676930 . _:b414677720 "2"^^ . _:b414676941 . _:b414677723 "2"^^ . _:b414676940 . _:b414676889 . _:b414677722 "2"^^ . _:b414676943 . _:b414677206 . _:b414677880 . _:b414677733 "2"^^ . _:b414676942 . _:b414677732 "2"^^ . _:b414676937 . _:b414677378 . _:b414677735 "2"^^ . _:b414676936 . . _:b414677734 "2"^^ . _:b414676939 . _:b414677729 "2"^^ . _:b414676938 . . . . _:b414677728 "2"^^ . _:b414676949 . _:b414677731 "2"^^ . _:b414677785 . _:b414676948 . _:b414677735 . . _:b414677730 "2"^^ . _:b414676951 . _:b414677627 . _:b414677741 "2"^^ . _:b414676950 . . _:b414677740 "2"^^ . _:b414676945 . . _:b414677758 . _:b414677743 "2"^^ . _:b414676944 . _:b6102642 . _:b414677742 "2"^^ . _:b414676947 . . _:b414677307 . _:b414677254 . _:b414677737 "2"^^ . _:b414676946 . _:b414677277 . _:b414677736 "2"^^ . _:b414676957 . _:b6102596 "results" . _:b414677321 . . _:b414676610 . _:b414677739 "2"^^ . . _:b414676956 . . _:b414677738 "2"^^ . _:b414676959 . . _:b414676467 . . _:b414677749 "2"^^ . _:b414676958 . _:b414677748 "2"^^ . _:b414676953 . . _:b414677539 . . _:b414677751 "2"^^ . _:b414676952 . . . _:b414677750 "2"^^ . . _:b414677821 . _:b414676955 . _:b414676350 . _:b414677745 "2"^^ . _:b414676954 . _:b414677744 "2"^^ . _:b414676965 . _:b414677405 . _:b414677630 . . _:b414677747 "2"^^ . _:b414676964 . . _:b414676921 . _:b414677746 "2"^^ . _:b414676967 . . _:b414677757 "2"^^ . _:b414676966 . . . . _:b414677756 "2"^^ . _:b414676961 . . _:b414677759 "2"^^ . _:b414676960 . _:b6102583 . _:b414676957 . _:b414677758 "2"^^ . _:b414676963 . . _:b414677753 "2"^^ . _:b414676962 . _:b414677787 . . _:b414677752 "2"^^ . _:b414676973 . . _:b414677755 "2"^^ . . _:b414676972 . . _:b414677754 "2"^^ . _:b414676975 . _:b414677513 . _:b414677765 "2"^^ . _:b414676974 . _:b414677715 . _:b414676499 . _:b414677764 "2"^^ . _:b414677032 . _:b414677590 . _:b414676969 . _:b414676646 . _:b414676328 . _:b414677767 "2"^^ . _:b414676968 . _:b414677766 "2"^^ . _:b414676971 . _:b414677760 . _:b414676448 . _:b414677761 "2"^^ . _:b414676299 "27"^^ . _:b414676970 . . _:b414677760 "2"^^ . _:b414676298 "27"^^ . _:b414676981 . . _:b414677763 "2"^^ . _:b414676980 . _:b414676297 "28"^^ . _:b414677762 "2"^^ . _:b414676983 . _:b414676296 "28"^^ . _:b414676725 . _:b414676601 . . . _:b414677773 "2"^^ . _:b414676982 . . _:b414676302 "25"^^ . _:b414677772 "2"^^ . _:b414676977 . _:b414676303 "24"^^ . _:b414676509 . . _:b414676301 "26"^^ . _:b414677775 "2"^^ . _:b414676976 . _:b414676300 "26"^^ . _:b414677774 "2"^^ . _:b414676979 . . _:b414677769 "2"^^ . _:b414676306 "23"^^ . _:b414676978 . . . _:b414676307 "22"^^ . _:b414677768 "2"^^ . _:b414676989 . _:b414676935 . _:b414677771 "2"^^ . _:b414676988 . _:b414676304 "24"^^ . . _:b414677770 "2"^^ . _:b414676305 "23"^^ . _:b414676991 . . _:b414677781 "2"^^ . _:b414676990 . _:b414676309 "20"^^ . . _:b414677780 "2"^^ . _:b414676985 . _:b414676308 "21"^^ . . . _:b414677783 "2"^^ . _:b414676984 . _:b414676311 "20"^^ . . _:b414677782 "2"^^ . _:b414676987 . _:b414676310 "20"^^ . _:b414676841 . _:b414676540 . . _:b414677777 "2"^^ . _:b414676313 "19"^^ . _:b414676986 . _:b414676293 "37"^^ . . _:b414677776 "2"^^ . _:b414676485 . _:b414676312 "20"^^ . _:b414676315 "18"^^ . _:b414677779 "2"^^ . _:b414676484 . _:b414676292 "40"^^ . _:b414676295 "30"^^ . _:b414676314 "19"^^ . _:b414677778 "2"^^ . _:b414676294 "35"^^ . _:b414676487 . _:b414676317 "18"^^ . _:b414677789 "2"^^ . _:b414676486 . _:b414676316 "18"^^ . _:b414677788 "2"^^ . _:b414676982 . _:b414677651 . _:b414676481 . _:b414676944 . _:b414677791 "2"^^ . _:b414676480 . . . _:b414676318 "18"^^ . _:b414677790 "2"^^ . _:b414676483 . _:b414676319 "17"^^ . _:b414677785 "2"^^ . _:b414676482 . _:b414676320 "17"^^ . _:b414677660 . _:b414677784 "2"^^ . _:b414676493 . _:b414676321 "16"^^ . . _:b414677146 . _:b414677787 "2"^^ . _:b414676492 . _:b414676322 "16"^^ . _:b414677786 "2"^^ . _:b414676495 . _:b414676323 "16"^^ . . _:b414676324 "15"^^ . _:b414677797 "2"^^ . _:b414676494 . _:b414677082 . _:b414676325 "15"^^ . _:b414677796 "2"^^ . _:b414676489 . _:b414676647 . . _:b414676796 . _:b414676326 "15"^^ . _:b414677799 "2"^^ . _:b414676488 . _:b414676327 "14"^^ . _:b414677798 "2"^^ . _:b414676491 . _:b6102577 "In an autoimmune setting, PD-1 is essential for maintaining T cell anergy and preventing autoimmunity >>10<<,11. Genetic deletion of PD-1 results in profound and complex multi-organ autoimmune destruction 4. Similarly, blocking PD-1-PD-L1 interactions accelerates spontaneous autoimmune diabetes 12 and reverses immune tolerance 10,11. Together" . . . . _:b414676328 "14"^^ . . _:b414677793 "2"^^ . _:b414677532 . . _:b414676490 . _:b414676335 "12"^^ . _:b414676329 "14"^^ . _:b414677230 . _:b414677792 "2"^^ . _:b414676501 . _:b414676334 "12"^^ . . _:b414677795 "2"^^ . _:b414676500 . _:b414676333 "12"^^ . _:b414677150 . _:b414677794 "2"^^ . _:b414676503 . _:b414676332 "13"^^ . . _:b414677805 "2"^^ . _:b414676502 . _:b414677061 . _:b414676331 "13"^^ . _:b414677804 "2"^^ . _:b414676497 . _:b414676330 "13"^^ . _:b414677807 "2"^^ . _:b414676496 . . _:b414676395 . . _:b414677806 "2"^^ . . _:b414676499 . . _:b414676343 "11"^^ . _:b414677801 "2"^^ . _:b414676498 . . _:b414676342 "11"^^ . _:b414677800 "2"^^ . _:b414676509 . _:b414676341 "11"^^ . _:b414677803 "2"^^ . _:b414676508 . _:b414676623 . _:b414676340 "11"^^ . _:b414677802 "2"^^ . _:b414676511 . _:b414677813 "2"^^ . _:b414676510 . _:b414676339 "12"^^ . _:b414677523 . _:b414677812 "2"^^ . _:b414676505 . _:b414676338 "12"^^ . _:b414676790 . _:b6102660 . _:b414677815 "2"^^ . _:b414676504 . _:b414676337 "12"^^ . _:b414677814 "2"^^ . _:b414676507 . _:b414676336 "12"^^ . _:b414676351 "10"^^ . . _:b414677809 "2"^^ . _:b414677646 . _:b414677634 . _:b414676506 . . _:b414676350 "10"^^ . _:b414677808 "2"^^ . _:b414676517 . . . _:b6102656 . _:b414676349 "10"^^ . . _:b414677811 "2"^^ . _:b414677161 . _:b414676516 . _:b414676348 "10"^^ . _:b414677810 "2"^^ . _:b414676519 . _:b414676699 . . _:b414676347 "10"^^ . _:b6102658 . _:b414677821 "2"^^ . _:b414676518 . . _:b414676346 "10"^^ . _:b414677820 "2"^^ . _:b414676513 . _:b414676345 "10"^^ . . _:b414677823 "2"^^ . _:b414676512 . . _:b414676344 "11"^^ . _:b414677822 "2"^^ . _:b414676515 . _:b414677817 "2"^^ . _:b414676514 . _:b414676358 "9"^^ . _:b414677745 . . _:b414677816 "2"^^ . _:b414676525 . _:b414676359 "9"^^ . _:b6102642 "Early reports suggested that initial interactions during the first phase of T cell activation tend to be transient [5-10 minutes during the first 3-15 hours 20,21,>>40<<]. However, a more recent report found that long lived T cell-DC interactions could occur following the initial T cell-DC contact and that prolonged interactions were required for T cell activation 41. In this study, Erk phosphorylation" . _:b414677819 "2"^^ . _:b414676524 . _:b414676356 "9"^^ . . . . . _:b414677818 "2"^^ . _:b414676527 . _:b414676704 . . _:b414676357 "9"^^ . _:b414677829 "2"^^ . _:b414676526 . _:b414676354 "9"^^ . . _:b414677828 "2"^^ . _:b414676521 . . _:b414676355 "9"^^ . _:b414676353 "10"^^ . _:b414677678 . _:b414677831 "2"^^ . _:b414676520 . _:b414676352 "10"^^ . _:b6102620 . _:b414677830 "2"^^ . _:b414676523 . _:b414676993 . _:b414677825 "2"^^ . _:b414676366 "8"^^ . _:b414676522 . . _:b414677824 "2"^^ . _:b414676367 "8"^^ . _:b414676650 . _:b414676533 . _:b414677827 "2"^^ . _:b414676296 . _:b414677218 . _:b414676532 . _:b414676364 "9"^^ . _:b414677826 "2"^^ . _:b414676535 . _:b414676365 "9"^^ . _:b414677837 "2"^^ . _:b414676534 . _:b414676362 "9"^^ . _:b414676835 . _:b414677836 "2"^^ . _:b414676529 . _:b414676363 "9"^^ . _:b414677839 "2"^^ . _:b414676528 . _:b414676360 "9"^^ . _:b414677068 . . . _:b414677838 "2"^^ . _:b414676531 . _:b414676361 "9"^^ . . _:b414677833 "2"^^ . _:b414676374 "8"^^ . _:b6102610 . _:b414676582 . _:b414676530 . . _:b414676471 . _:b414677832 "2"^^ . _:b414676375 "8"^^ . _:b414676678 . _:b414676541 . _:b414677835 "2"^^ . _:b414676372 "8"^^ . _:b414676540 . _:b414676473 . _:b414676706 . _:b414677834 "2"^^ . _:b414676373 "8"^^ . _:b414676543 . _:b414676363 . . _:b414677845 "2"^^ . _:b414676370 "8"^^ . _:b414676542 . _:b414676999 . _:b414677844 "2"^^ . _:b414676371 "8"^^ . _:b414676537 . _:b414677847 "2"^^ . _:b414676368 "8"^^ . _:b414676536 . _:b6102604 . . _:b414677846 "2"^^ . _:b414677647 . _:b414676369 "8"^^ . _:b414677135 . _:b414676539 . _:b414676382 "7"^^ . _:b414677841 "2"^^ . . _:b414676576 . _:b414676538 . _:b414676383 "7"^^ . _:b414677840 "2"^^ . _:b414676529 . . _:b414676549 . _:b6102603 . _:b414677843 "2"^^ . _:b414676380 "8"^^ . . _:b414676548 . . _:b414676381 "7"^^ . _:b414677842 "2"^^ . _:b414677552 . _:b414676551 . _:b6102601 . _:b414676562 . _:b414677853 "2"^^ . _:b414676378 "8"^^ . _:b414676550 . _:b414677852 "2"^^ . _:b414676379 "8"^^ . . _:b414676545 . . . _:b414677855 "2"^^ . _:b414676376 "8"^^ . _:b414676544 . . _:b414677518 . _:b414677854 "2"^^ . _:b414676377 "8"^^ . . _:b414676547 . . _:b414676390 "7"^^ . _:b414677849 "2"^^ . _:b414676546 . _:b414676391 "7"^^ . _:b414677848 "2"^^ . _:b414676795 . _:b414676557 . _:b414676388 "7"^^ . _:b414677851 "2"^^ . . _:b414676556 . . . _:b414676389 "7"^^ . _:b414677850 "2"^^ . _:b414676559 . _:b414677613 . . . _:b414676386 "7"^^ . _:b414677861 "2"^^ . . _:b414676558 . _:b414676387 "7"^^ . _:b414677860 "2"^^ . _:b414677044 . _:b414676553 . _:b414677824 . _:b414676384 "7"^^ . _:b414677863 "2"^^ . _:b414676552 . _:b414676385 "7"^^ . _:b414677862 "2"^^ . _:b414676555 . _:b414676398 "7"^^ . _:b414677857 "2"^^ . _:b414676554 . _:b414676399 "7"^^ . _:b414677856 "2"^^ . _:b414676308 . _:b414676565 . _:b414676765 . _:b414676396 "7"^^ . _:b414677859 "2"^^ . _:b414676564 . . _:b414677501 . _:b414676397 "7"^^ . _:b414677858 "2"^^ . _:b414676567 . _:b6102585 "Previously, we have used a well-defined, antigen-specific tolerance model to examine the cellular basis of immunological tolerance using antigen-pulsed and fixed antigen-presenting cells (APC) >>10<<. We determined that the administration of islet antigen peptide mimic, p31, coupled to chemically fixed APCs reversed diabetes and induced a robust, long-term inactivation of islet-specific, BDC2.5 TCR transgenic T cells." . . _:b414677861 . . _:b414676394 "7"^^ . _:b414677869 "2"^^ . _:b414677255 . _:b414676566 . . _:b414677544 . _:b414676395 "7"^^ . _:b414677868 "2"^^ . _:b414676561 . . _:b414676392 "7"^^ . _:b414677871 "2"^^ . _:b414676560 . _:b414676651 . _:b414676393 "7"^^ . _:b414677870 "2"^^ . . . _:b414676563 . . _:b414676406 "6"^^ . . _:b414677865 "2"^^ . _:b414677516 . _:b414676562 . . _:b414676407 "6"^^ . _:b414676603 . _:b414677864 "2"^^ . _:b414676573 . . _:b414677773 . _:b414676404 "7"^^ . _:b414677867 "2"^^ . _:b414676863 . _:b414676572 . _:b414677245 . . _:b414676405 "7"^^ . _:b414677866 "2"^^ . _:b414676575 . _:b414676948 . _:b414676402 "7"^^ . _:b414677877 "2"^^ . . _:b414676574 . _:b414676403 "7"^^ . _:b414677876 "2"^^ . _:b414676569 . _:b414677332 . _:b414676400 "7"^^ . _:b414677879 "2"^^ . _:b414676568 . _:b414676401 "7"^^ . _:b414677878 "2"^^ . . . _:b414676571 . _:b414676414 "6"^^ . _:b6102590 . _:b414677873 "2"^^ . . . _:b414676570 . _:b414676415 "6"^^ . _:b6102634 . _:b414677872 "2"^^ . _:b414676581 . _:b414676412 "6"^^ . . _:b414677875 "2"^^ . _:b414676580 . _:b414676413 "6"^^ . _:b6102589 . _:b414677231 . _:b414677874 "2"^^ . _:b414676583 . _:b414676410 "6"^^ . _:b414677885 "2"^^ . _:b414676582 . _:b414676411 "6"^^ . _:b414677884 "2"^^ . _:b414676577 . . _:b414676408 "6"^^ . _:b414677887 "2"^^ . _:b414676576 . _:b414676997 . . _:b414676375 . _:b414677199 . _:b414676409 "6"^^ . . _:b414677886 "2"^^ . _:b414676579 . _:b414676422 "6"^^ . _:b414677881 "2"^^ . _:b414676578 . _:b414676423 "6"^^ . _:b6102626 . . _:b414677880 "2"^^ . _:b414677688 . _:b414676589 . _:b414677629 . _:b414676420 "6"^^ . _:b414677883 "2"^^ . _:b414676588 . . _:b414676421 "6"^^ . _:b414677882 "2"^^ . _:b414676591 . _:b414676418 "6"^^ . . _:b414677740 . _:b414677893 "2"^^ . . _:b414676590 . _:b414676419 "6"^^ . . _:b414677892 "2"^^ . _:b414676585 . . _:b414677220 . _:b414676416 "6"^^ . _:b414677827 . _:b414677895 "2"^^ . _:b414676584 . _:b414676417 "6"^^ . _:b414677894 "2"^^ . _:b414676587 . _:b414676430 "6"^^ . _:b414677889 "2"^^ . _:b414676586 . _:b414676450 . _:b414676431 "6"^^ . . _:b414677888 "2"^^ . _:b414676597 . _:b414676533 . _:b414676428 "6"^^ . _:b414677891 "2"^^ . _:b414676596 . . _:b414676429 "6"^^ . . _:b414677890 "2"^^ . _:b414676599 . . _:b414676426 "6"^^ . _:b6102639 . _:b414677184 . _:b414676309 . _:b414676598 . _:b414676427 "6"^^ . . _:b414676593 . _:b414676424 "6"^^ . _:b414676592 . . _:b414676425 "6"^^ . _:b414676595 . _:b414676438 "6"^^ . . _:b414676594 . . _:b414676439 "6"^^ . _:b414677896 "2"^^ . _:b6102588 . _:b414676605 . _:b414676436 "6"^^ . _:b414676604 . _:b414676437 "6"^^ . _:b414676607 . . _:b414676434 "6"^^ . _:b414676606 . _:b414676643 . _:b414676435 "6"^^ . _:b414676369 . _:b414676601 . _:b414676432 "6"^^ . _:b414676452 . _:b414676881 . . _:b414676600 . _:b414676433 "6"^^ . . _:b414676603 . _:b414676446 "6"^^ . . _:b414676602 . _:b414676447 "6"^^ . _:b414676381 . _:b414676613 . _:b414677156 . _:b414676444 "6"^^ . _:b414676519 . _:b414676612 . _:b414676445 "6"^^ . . _:b414676615 . _:b414676442 "6"^^ . _:b414677075 . _:b6102636 "discussion" . _:b414676614 . _:b414676443 "6"^^ . . . _:b414676609 . _:b414676685 . _:b414676440 "6"^^ . _:b414677654 . _:b414676608 . . _:b414676441 "6"^^ . . _:b414676611 . _:b414676543 . _:b414676610 . _:b414676453 "5"^^ . . _:b414676621 . . _:b414676452 "5"^^ . . _:b414676620 . _:b414676455 "5"^^ . _:b414677299 . . _:b414676623 . _:b414676454 "5"^^ . _:b414677605 . . _:b414677870 . _:b414676622 . . . . _:b414676617 . _:b414676448 "6"^^ . _:b414676616 . _:b414676451 "5"^^ . _:b414677225 . _:b414676449 "6"^^ . _:b414676619 . _:b414676450 "5"^^ . . _:b414677728 . . . _:b414676618 . _:b414676313 . _:b414676461 "5"^^ . . _:b414676629 . _:b6102588 . _:b414676460 "5"^^ . _:b414676360 . _:b414676628 . _:b414676463 "5"^^ . . . _:b414676631 . _:b414676462 "5"^^ . _:b414676630 . _:b414676457 "5"^^ . _:b414677359 . _:b414676625 . _:b414676456 "5"^^ . _:b414676624 . . _:b414676459 "5"^^ . . . _:b414676627 . _:b414676458 "5"^^ . _:b414676626 . _:b414676469 "5"^^ . _:b414676637 . _:b414676468 "5"^^ . . _:b414676636 . _:b414676471 "5"^^ . _:b414676639 . _:b414676470 "5"^^ . _:b414676502 . _:b414676638 . _:b414676465 "5"^^ . . _:b414676633 . _:b414676464 "5"^^ . _:b414676632 . _:b414676467 "5"^^ . _:b414676847 . _:b414676422 . _:b414676454 . . _:b414676635 . . _:b414676466 "5"^^ . _:b414676634 . _:b414676477 "5"^^ . _:b414676969 . _:b414676645 . _:b414676436 . _:b414676476 "5"^^ . _:b414676644 . . _:b414676479 "5"^^ . . _:b414677152 . _:b414676647 . _:b414676478 "5"^^ . _:b414676646 . _:b414677857 . _:b414676473 "5"^^ . . _:b414676536 . _:b6102646 . _:b414676490 . _:b414676641 . _:b414677201 . _:b414677059 . _:b414676472 "5"^^ . _:b414677892 . _:b414676843 . . . _:b414676800 . _:b414676640 . _:b414676475 "5"^^ . . _:b414676626 . _:b6102638 . _:b414677742 . _:b414676643 . _:b414676474 "5"^^ . _:b414676434 . _:b414676663 . _:b414676642 . _:b6102633 "Islets were isolated as previously reported >>49<<. Briefly, a 3-ml collagenase P (Roche) solution (0.75 mg/ml) was injected into the pancreatic duct of 4-wk-old NOD." . _:b414676653 . _:b414676652 . _:b414676655 . _:b414676532 . _:b414676654 . _:b414676649 . . _:b414676648 . _:b414677881 . _:b414677483 . _:b414676651 . _:b414676650 . . _:b414677416 . _:b414676661 . _:b414677296 . _:b414677531 . _:b414676660 . . _:b414676663 . _:b414677261 . _:b414676662 . _:b414676657 . . . _:b414676656 . _:b414676996 . _:b414676659 . . . . _:b414676658 . . _:b414676723 . . . . _:b414676669 . . _:b414676668 . . . _:b414676671 . . . _:b414676670 . . _:b414676833 . . _:b414677224 . _:b414676665 . _:b414676963 . _:b414676349 . _:b414676664 . _:b414677724 . . . _:b414676667 . . . _:b414676666 . _:b414676677 . _:b414676476 . . _:b414676358 . . _:b414676676 . . _:b414677073 . _:b414676679 . _:b414677010 . . _:b414676678 . _:b414676673 . . . _:b414676672 . . . _:b414676675 . _:b414676674 . _:b414676685 . _:b414677182 . _:b414676684 . _:b414676687 . _:b414676942 . _:b414676686 . _:b414676372 . _:b414676681 . _:b414676472 . _:b414677798 . _:b414676680 . _:b414676683 . _:b414676682 . _:b414677685 . _:b414676693 . _:b414676449 . . . . _:b414676692 . . _:b414676351 . _:b414676695 . _:b414677594 . _:b414676694 . _:b414676689 . . _:b414676688 . _:b414676583 . _:b414676691 . . . . _:b414677030 . _:b414676690 . _:b414676294 . _:b414676701 . _:b414676838 . _:b414676700 . _:b414677270 . _:b6102630 "Anti-CTLA-4 (UC4F10), and anti-CTLA-4 Fab fragments were made as described previously >>1<<. Mice were injected intraperitoneally with 250 \u03BCg anti\u2013PD-L1, anti\u2013PD-L2, anti-B7-1, anti-PD-1, or anti-CTLA-4 as indicated." . _:b414676703 . _:b414676702 . . _:b414676697 . . _:b414676696 . _:b414676699 . _:b414676698 . _:b6102569 "CTLA-4 is rapidly expressed on the surface of T cells following activation and is highly upregulated by engagement of the co-stimulatory molecule CD28 >>1<<. CTLA-4 ligation antagonizes early T cell activation leading to decreased interleukin 2 (IL-2) production, inhibition of cell cycle progression and modulation of TCR signaling 2,3. CTLA-4 and CD28 shares the ligands B7-1 (also called" . . . _:b414676709 . _:b414676609 . _:b414676708 . _:b414676711 . _:b414676710 . _:b414677795 . _:b414676705 . _:b414676704 . . . _:b414677588 . _:b414676632 . _:b414676707 . . . . _:b414676706 . . _:b414676717 . _:b6102583 "In addition, PD-1 may directly recruit phosphatases such as SHP-1, SHP-2 and PP2A, which interfere with TCR signaling 4,>>14<<-16. However, the effects of PD-1 engagement during T cell activation are unclear as in vitro models do not adequately demonstrate the inhibitory activity of PD-1 17. In vivo studies of PD-1\u2013mediated inhibition have been limited to global" . _:b414676716 . . _:b414676748 . . _:b414676504 . . _:b414676719 . _:b414677065 . _:b414677733 . _:b414676997 "2"^^ . _:b414676718 . . _:b6102655 . _:b414676996 "2"^^ . . _:b414676713 . _:b414676999 "2"^^ . _:b6102589 "Na\u00EFve circulating T cells enter the LN through high endothelial venules and move on a network of stromal cells called fibroblastic reticular cells (FRCs), which define the potential location and migratory range of T cells >>24<<. The FRC also provide a substrate for resident DCs to sample and display antigen to passing T cells. As T cells migrate along the FRC highway they probe DCs for signals and antigen 24. Initial interactions may be transient, but antigen" . _:b414676712 . _:b414676998 "2"^^ . _:b414676715 . _:b414676645 . . _:b414676993 "2"^^ . _:b414676714 . _:b414676821 . _:b414676992 "2"^^ . _:b414676725 . . _:b414677675 . _:b414676995 "2"^^ . _:b414676724 . _:b414677623 . _:b414676846 . _:b414676994 "2"^^ . _:b6102592 "Initial interactions may be transient, but antigen recognition results in T cell swarming, formation of stable T cell-DC conjugates, and T cell arrest 25,>>26<<. TCR ligation results in \u2018stop signals\u2019 that decrease T cell motility and are required for stable T cell-DC conjugate formation and development of the immunological synapse 21,26. Prolonged T cell-DC interactions are critical for full T" . . _:b414676727 . _:b414677005 "2"^^ . . _:b414676726 . _:b414677004 "2"^^ . _:b414676721 . _:b414677007 "2"^^ . _:b414676720 . . _:b414677006 "2"^^ . _:b414676723 . _:b414677001 "2"^^ . _:b414676722 . _:b414677000 "2"^^ . _:b414676733 . . _:b414677003 "2"^^ . _:b414676531 . _:b414676732 . _:b414677002 "2"^^ . _:b414676735 . _:b6102622 . _:b414676555 . _:b414676741 . _:b414677013 "2"^^ . _:b414676734 . _:b414677012 "2"^^ . _:b414677292 . . _:b414676729 . . . . _:b414677015 "2"^^ . _:b414676728 . _:b414677014 "2"^^ . _:b414676731 . _:b414677768 . _:b414676929 . _:b414677009 "2"^^ . _:b414676730 . _:b414677008 "2"^^ . _:b414677011 "2"^^ . _:b414676984 . _:b414677010 "2"^^ . _:b6102606 . _:b414677021 "2"^^ . _:b414677817 . _:b414677020 "2"^^ . _:b414677037 . _:b414677862 . _:b414677023 "2"^^ . _:b414677022 "2"^^ . _:b414677017 "2"^^ . _:b414676888 . . _:b414677016 "2"^^ . . . _:b414677019 "2"^^ . _:b414677330 . . _:b414676980 . _:b414676553 . _:b414677018 "2"^^ . _:b6102645 "The second phase subsequently results in longer lived contacts where T cells form stable conjugates and begin to secrete cytokines which transitions into a third phase of high motility and rapid proliferation >>21<<. Our studies demonstrated that PD-1 blockade restored stable T cell-DC contacts, Erk phosphorylation, IFN-\u03B3 production and, most importantly, T1D. These findings suggest that PD-1 normally functions to prevent the T cell stop signal and" . _:b414677029 "2"^^ . _:b414676588 . _:b414677028 "2"^^ . _:b414677031 "2"^^ . . _:b414677030 "2"^^ . . _:b414677420 . _:b414677025 "2"^^ . _:b414677024 "2"^^ . _:b414677458 . _:b414677027 "2"^^ . _:b6102599 . _:b414677026 "2"^^ . _:b414677037 "2"^^ . _:b414676479 . . _:b414677036 "2"^^ . . _:b414677039 "2"^^ . . _:b414677038 "2"^^ . _:b414677033 "2"^^ . _:b414677032 "2"^^ . . _:b414677035 "2"^^ . . . _:b414677034 "2"^^ . _:b414677358 . _:b414676595 . . _:b414677079 . _:b414677045 "2"^^ . . _:b414677044 "2"^^ . _:b414677499 . . _:b414676310 . _:b414677047 "2"^^ . _:b414677034 . _:b414677046 "2"^^ . . _:b414677041 "2"^^ . . _:b414677040 "2"^^ . _:b414677799 . _:b414677043 "2"^^ . _:b414677042 "2"^^ . _:b414677389 . _:b414677053 "2"^^ . . . _:b414676311 . _:b414676312 . _:b414677052 "2"^^ . . _:b414677055 "2"^^ . _:b414677054 "2"^^ . _:b414676560 . _:b414677806 . _:b414677049 "2"^^ . _:b414676548 . _:b414677048 "2"^^ . _:b414677051 "2"^^ . _:b414677050 "2"^^ . _:b414676670 . _:b414677663 . _:b414677061 "2"^^ . . . _:b414677060 "2"^^ . _:b414677063 "2"^^ . _:b414676296 . _:b414676805 . _:b414676297 . _:b414677114 . _:b414676298 . . . _:b414676299 . _:b414677062 "2"^^ . . . _:b414676300 . _:b414676301 . _:b414676302 . . _:b414676303 . _:b414677057 "2"^^ . . _:b414677056 "2"^^ . _:b414677092 . _:b414676292 . _:b414676293 . _:b414676294 . _:b414676405 . _:b414676295 . _:b414677431 . _:b414677059 "2"^^ . _:b414676312 . _:b414676313 . _:b414677086 . _:b414676314 . _:b414676315 . _:b414677058 "2"^^ . _:b414676316 . _:b414676317 . _:b414676318 . _:b414676319 . _:b414677069 "2"^^ . _:b414676304 . _:b414676305 . _:b414676306 . _:b414676307 . . _:b414677068 "2"^^ . _:b414677648 . _:b414676308 . _:b414676309 . _:b414676676 . _:b414676310 . _:b414676311 . _:b414677071 "2"^^ . _:b414676328 . . . _:b414676329 . _:b414676330 . _:b414676331 . _:b414677247 . _:b414677070 "2"^^ . _:b414676655 . _:b414676332 . _:b414676333 . _:b414676334 . _:b414676335 . _:b414677065 "2"^^ . _:b414676320 . _:b414676321 . _:b414677126 . _:b414676322 . _:b414676323 . _:b414677297 . _:b414677064 "2"^^ . . _:b414676324 . _:b414676325 . _:b414676326 . _:b414676327 . _:b414677504 . _:b414677067 "2"^^ . _:b414676344 . _:b414676345 . _:b414676346 . _:b414676347 . _:b414677066 "2"^^ . _:b414677887 . _:b414676348 . _:b414676349 . . _:b414676350 . _:b6102572 . _:b414676351 . _:b414677077 "2"^^ . _:b414676336 . _:b414676337 . _:b414676338 . _:b414676339 . _:b414677076 "2"^^ . _:b414676340 . _:b414676341 . _:b414676342 . _:b414676343 . _:b414677079 "2"^^ . . _:b414676360 . _:b414676361 . _:b414676362 . _:b414676363 . _:b414677078 "2"^^ . _:b414676364 . _:b414676365 . _:b414676366 . _:b414676367 . _:b414677073 "2"^^ . _:b414676352 . _:b414676353 . _:b414676354 . _:b414676355 . _:b414677072 "2"^^ . _:b414676356 . _:b414676293 . _:b414676357 . _:b414676358 . _:b414676359 . _:b414677075 "2"^^ . _:b414676376 . _:b414676292 . _:b414676377 . _:b414676378 . _:b414676379 . _:b414677074 "2"^^ . _:b414676380 . _:b414676295 . _:b414676381 . _:b414676382 . _:b414676383 . _:b414677085 "2"^^ . _:b414676368 . _:b414676294 . _:b414676369 . _:b414677060 . _:b414676370 . _:b414676371 . _:b414677084 "2"^^ . _:b414677866 . _:b414676372 . _:b414676373 . _:b414676374 . _:b414677765 . _:b414676375 . _:b414677087 "2"^^ . _:b414676392 . _:b414676458 . _:b414676393 . _:b414676394 . _:b414677764 . _:b414676395 . _:b414677086 "2"^^ . _:b414676396 . _:b414676397 . _:b414676398 . _:b414677767 . _:b414676399 . _:b414677081 "2"^^ . _:b414676384 . _:b414676385 . _:b414676386 . _:b414677766 . _:b414676387 . _:b414676882 . _:b414677080 "2"^^ . _:b414676388 . _:b414676301 . _:b414676389 . _:b414676390 . _:b414677761 . . _:b414676391 . _:b414677083 "2"^^ . _:b414676633 . _:b414676408 . _:b414676300 . _:b414676409 . _:b414676410 . _:b414677760 . _:b414676411 . _:b414677082 "2"^^ . _:b414676412 . _:b414676303 . _:b414676413 . . _:b414677763 . _:b414676414 . _:b414676664 . _:b414676415 . _:b414677093 "2"^^ . _:b414676400 . _:b414676365 . _:b414676401 . _:b414676302 . _:b414676402 . _:b414677762 . _:b414676403 . _:b414677092 "2"^^ . _:b414676404 . _:b414676297 . _:b414676405 . . _:b414677773 . _:b414676406 . _:b414676407 . _:b414677095 "2"^^ . _:b414677496 . _:b414676424 . _:b414676296 . _:b414676425 . _:b414676426 . _:b414677772 . . _:b414676427 . _:b414677094 "2"^^ . _:b414676428 . _:b414676299 . _:b414676429 . _:b414676430 . _:b414677775 . _:b414676431 . _:b414677089 "2"^^ . _:b414676416 . _:b414676298 . _:b414676417 . _:b414676418 . _:b414677774 . _:b414676419 . _:b414677088 "2"^^ . _:b414676420 . _:b414676309 . _:b414676421 . _:b414676422 . _:b414677769 . . _:b414676423 . _:b414677091 "2"^^ . _:b414677373 . _:b414676440 . _:b414676308 . _:b414676441 . _:b414676442 . _:b414677768 . _:b414676443 . _:b414677090 "2"^^ . _:b414676444 . _:b414676311 . _:b414677561 . _:b414676445 . _:b414676446 . _:b414677771 . _:b414676447 . _:b414677101 "2"^^ . _:b414676432 . _:b414676310 . _:b414676433 . _:b414676434 . _:b414677770 . _:b414676435 . _:b414677527 . _:b414677100 "2"^^ . . _:b414676436 . _:b414676305 . _:b414676437 . _:b414676438 . _:b6102580 "Similarly, blocking PD-1-PD-L1 interactions accelerates spontaneous autoimmune diabetes 12 and reverses immune tolerance >>10<<,11. Together these data support a central role for PD-1 as a major inhibitory pathway controlling immunity and suggest that exhaustion and peripheral tolerance are linked mechanistically." . _:b414677781 . _:b414676439 . _:b414677103 "2"^^ . . _:b414676456 . _:b414676304 . _:b414676505 . . _:b414676457 . _:b414676458 . _:b414677780 . _:b414676459 . _:b414677713 . _:b414677102 "2"^^ . _:b414676460 . . _:b414676307 . _:b414676461 . _:b414676462 . _:b414677783 . _:b414676567 . _:b414676463 . _:b414677097 "2"^^ . _:b414676448 . _:b414676306 . _:b414676449 . _:b414676450 . _:b414677782 . _:b414676451 . _:b414677096 "2"^^ . _:b414676452 . _:b414676317 . _:b414676453 . _:b414676454 . _:b414677777 . _:b414676455 . . _:b414677099 "2"^^ . _:b414676472 . _:b414676316 . _:b414676473 . _:b414676474 . _:b6102614 "Prolonged interactions between T cells and DCs is critical for full T cell activation >>27<<,29. We hypothesized that PD-1 normally functions to prevent the stable T cell-DC contacts that are required for full T cell activation. To test this notion, we used the adoptive transfer and imaging system described above to measure the" . _:b414677776 . _:b414677701 . _:b414676475 . _:b414677098 "2"^^ . _:b414676476 . _:b414676319 . _:b414676477 . _:b414676478 . _:b414677779 . _:b414676479 . _:b414677109 "2"^^ . _:b414676464 . _:b414676318 . _:b414677403 . _:b414676465 . _:b414676466 . _:b414677778 . _:b414676467 . _:b414677108 "2"^^ . _:b414676468 . _:b414676313 . _:b414676469 . . _:b414677789 . _:b414676470 . _:b414676471 . _:b414677111 "2"^^ . _:b414676312 . _:b414676729 . _:b414677788 . _:b414677110 "2"^^ . _:b414676315 . _:b414677791 . _:b414677300 . _:b414677105 "2"^^ . _:b414676314 . _:b414677790 . . _:b414677104 "2"^^ . _:b414676325 . _:b414677785 . _:b414677382 . _:b414677107 "2"^^ . _:b414676324 . . _:b414677784 . . _:b414677106 "2"^^ . _:b414676327 . . _:b414677703 . _:b414677787 . _:b414677117 "2"^^ . _:b414676326 . _:b414677786 . _:b414677116 "2"^^ . _:b414677656 . _:b414676321 . . _:b414677797 . _:b414677119 "2"^^ . _:b414676320 . . _:b414677796 . _:b414677118 "2"^^ . . _:b414676323 . _:b414677799 . _:b414677113 "2"^^ . _:b414676322 . _:b414677798 . _:b414677120 . _:b414677112 "2"^^ . _:b414676333 . _:b414676305 . _:b414677793 . _:b414677637 . _:b414677571 . . _:b414677115 "2"^^ . _:b414676332 . _:b414677792 . _:b414677340 . _:b414677114 "2"^^ . _:b414677440 . _:b414676335 . _:b414677795 . _:b414677125 "2"^^ . _:b414676334 . . _:b414677794 . _:b414677124 "2"^^ . _:b414676329 . . _:b414677805 . . _:b414677127 "2"^^ . _:b414676328 . _:b414677804 . _:b414677126 "2"^^ . _:b414676331 . _:b414677807 . _:b414677121 "2"^^ . _:b414677640 . _:b414676330 . _:b414676506 . _:b414677806 . _:b414677120 "2"^^ . _:b414676341 . _:b414677801 . _:b414677123 "2"^^ . _:b414676340 . _:b414677800 . _:b414677122 "2"^^ . . _:b414676960 . _:b414676343 . _:b414677803 . . _:b414677133 "2"^^ . _:b414676342 . _:b414676690 . _:b414677802 . _:b414677132 "2"^^ . _:b414676337 . _:b414677813 . _:b414677135 "2"^^ . _:b414676336 . _:b414677812 . _:b414677134 "2"^^ . _:b414676339 . . _:b414677815 . _:b414677129 "2"^^ . _:b414676719 . _:b414676896 . _:b414677158 . _:b414676338 . _:b414677814 . _:b414677128 "2"^^ . _:b414677293 . _:b414676349 . _:b414676465 . _:b414677809 . _:b414677131 "2"^^ . _:b414676534 . _:b414676348 . _:b414676394 . _:b414677808 . _:b414676804 . _:b414676962 . _:b414677130 "2"^^ . . _:b414676351 . . _:b414676735 . _:b414677811 . . . _:b414677141 "2"^^ . _:b414676350 . _:b414677810 . . _:b414677736 . _:b414677718 . _:b414677140 "2"^^ . _:b414676345 . _:b414677668 . . _:b414677821 . _:b414677450 . _:b414677143 "2"^^ . _:b414676344 . _:b414677820 . _:b6102651 "Like PD-1, CTLA-4 can interact with SHP-1 and SHP-2 >>14<<. Unlike PD-1, CTLA-4 can also interact with the phosphatase PP2a 15." . _:b414677142 "2"^^ . _:b414676347 . _:b414677470 . . _:b414677823 . . _:b414677485 . _:b414677137 "2"^^ . . _:b414676346 . _:b414677514 . _:b414677822 . . _:b414677136 "2"^^ . _:b414676357 . _:b414677817 . _:b414677139 "2"^^ . . _:b414676356 . _:b414677816 . _:b414676715 . _:b414677138 "2"^^ . _:b414676359 . _:b414677819 . _:b414677149 "2"^^ . _:b414676358 . . _:b414677818 . _:b414676675 . _:b414677148 "2"^^ . _:b414676353 . _:b414677829 . _:b414677151 "2"^^ . _:b414676869 . _:b414676352 . _:b414677828 . _:b414677150 "2"^^ . _:b414676355 . . . _:b414677831 . _:b414677145 "2"^^ . _:b414676354 . _:b414677830 . _:b6102648 "Blockade of CTLA-4\u2013B7 interactions can prevent induction of tolerance by peptide-pulsed fixed APCs but could not reverse tolerance once established >>10<<. It is important to note that the same dose of blocking CTLA-4\u2013specific antibody was used in these MPLSM experiments as in a previous study that documented a critical role for CTLA-4 during the induction of tolerance 10." . _:b414677144 "2"^^ . . _:b414676365 . . _:b414677825 . _:b414677147 "2"^^ . . _:b414676364 . _:b414677336 . _:b414677824 . _:b414677146 "2"^^ . _:b414676367 . _:b414676952 . _:b414677827 . _:b414677157 "2"^^ . _:b414676366 . _:b414677826 . _:b414677156 "2"^^ . _:b414676361 . _:b414677837 . _:b414677159 "2"^^ . _:b414676360 . _:b414677836 . _:b414677158 "2"^^ . _:b414676363 . _:b414677324 . _:b414677839 . _:b414677153 "2"^^ . . _:b414676362 . . . _:b414677838 . _:b414677152 "2"^^ . . _:b414676373 . _:b414677171 . _:b414677833 . _:b414677155 "2"^^ . _:b414677190 . _:b414676372 . _:b414677832 . . _:b414677154 "2"^^ . _:b414676375 . _:b414677390 . _:b414677835 . _:b414677165 "2"^^ . _:b414676374 . _:b414677834 . _:b414677164 "2"^^ . . _:b414676369 . _:b414676656 . _:b414677845 . _:b414677167 "2"^^ . _:b414676368 . _:b414677844 . _:b414677166 "2"^^ . _:b414676371 . _:b414677194 . . _:b414677847 . _:b414677161 "2"^^ . _:b414676370 . _:b414677846 . _:b414676337 . _:b414677160 "2"^^ . _:b414676381 . _:b414677841 . . . _:b414677163 "2"^^ . _:b414676380 . _:b414677433 . _:b414677840 . _:b414677573 . . _:b414677162 "2"^^ . . . _:b414676383 . . _:b414677843 . . . _:b414677173 "2"^^ . _:b414676712 . _:b414676382 . _:b414676989 . _:b414677842 . _:b414677429 . _:b414677172 "2"^^ . . _:b414676377 . . _:b414677853 . _:b414676744 . _:b414677175 "2"^^ . _:b414676376 . _:b6102647 . _:b414676745 . _:b414676746 . _:b414677852 . _:b414677333 . _:b414676747 . _:b414676748 . _:b414677174 "2"^^ . _:b414676379 . _:b414676749 . . _:b414677855 . _:b414676750 . _:b414676751 . . _:b414677169 "2"^^ . _:b414676736 . _:b414676378 . _:b414676737 . _:b414676738 . _:b414677854 . _:b414676739 . _:b414677168 "2"^^ . _:b414676740 . _:b414676389 . _:b414676741 . _:b414677129 . _:b414677849 . _:b414676742 . _:b414676743 . _:b414677171 "2"^^ . _:b414676760 . _:b414676388 . _:b414676761 . _:b414676762 . _:b414677848 . _:b414676763 . _:b414677170 "2"^^ . _:b414676764 . _:b414676391 . _:b414676765 . _:b414676766 . _:b414677851 . . _:b414676767 . _:b414676752 . _:b414677181 "2"^^ . _:b414676390 . _:b414676753 . _:b414676754 . _:b414677850 . _:b414677197 . _:b414676673 . _:b414676755 . _:b414676756 . _:b414677180 "2"^^ . _:b414676724 . _:b414676385 . _:b414676757 . _:b414677081 . _:b414677861 . _:b414676758 . _:b414676524 . _:b414676759 . _:b414676776 . _:b414677183 "2"^^ . . _:b414676384 . _:b414676777 . _:b414676778 . _:b414677860 . _:b414676779 . _:b414677274 . . _:b414676780 . _:b414677182 "2"^^ . _:b414676387 . _:b414676781 . _:b414676782 . _:b414677863 . _:b414676783 . _:b414676768 . _:b414677177 "2"^^ . _:b414676386 . _:b414676769 . _:b414676770 . _:b414677862 . _:b414676771 . _:b414676772 . _:b414677176 "2"^^ . _:b414676397 . _:b414676773 . _:b414676774 . _:b414677857 . _:b414676775 . _:b414676792 . _:b414677179 "2"^^ . _:b414676396 . _:b414676793 . _:b414676794 . _:b414677856 . _:b414677553 . _:b414676909 . _:b414676795 . _:b414676796 . _:b414677178 "2"^^ . _:b414676399 . _:b414676797 . _:b414676586 . _:b414677859 . _:b414676798 . _:b414676799 . _:b414676784 . _:b414677189 "2"^^ . _:b414676398 . _:b414676785 . _:b414676786 . _:b414677858 . _:b414676787 . _:b414676788 . _:b414677188 "2"^^ . _:b414676393 . _:b414676789 . _:b414676790 . _:b414677869 . _:b414676791 . _:b414676808 . _:b6102620 "BDC2.5 TCR transgenic mice to Yeti mice, which express a YFP reporter cassette under the control of the IFN-\u03B3 promoter >>31<<. Tolerized BDC2.5.Thy1.1.Yeti T cells were transferred to recipient NOD mice and received isotype control antibody, anti-PD-L1, or anti-CTLA-4. PD-L1 blockade abrogated tolerance, and the majority of CD4+ T cells isolated directly from" . _:b414677741 . _:b414677401 . _:b414677191 "2"^^ . _:b414676392 . _:b414676809 . _:b414676810 . _:b414677868 . _:b414676811 . _:b414676812 . _:b414677190 "2"^^ . _:b414676376 . _:b414676813 . _:b414676395 . _:b414677055 . _:b414677871 . _:b414676814 . . _:b414676815 . _:b414676800 . _:b414677185 "2"^^ . _:b414676394 . _:b414676801 . _:b414676709 . _:b414677870 . _:b414676802 . _:b414676612 . _:b414676803 . _:b414676804 . _:b414677184 "2"^^ . . _:b414676405 . _:b414676805 . _:b414676806 . _:b414677865 . _:b414676807 . _:b414676824 . _:b414677187 "2"^^ . _:b414676404 . _:b414676825 . _:b414676826 . _:b414677864 . _:b414676380 . _:b414676827 . _:b414676828 . _:b414677186 "2"^^ . _:b414676742 . _:b414676829 . _:b414676407 . . _:b414677867 . _:b414677816 . _:b414676830 . _:b414676557 . _:b414676831 . . _:b414676816 . _:b414677197 "2"^^ . _:b414676406 . _:b414676817 . _:b414676818 . _:b414677866 . _:b414676513 . _:b414676819 . _:b414676820 . _:b414677196 "2"^^ . _:b414676401 . _:b414676821 . _:b414676822 . _:b414677877 . _:b414676823 . _:b414676840 . _:b414677199 "2"^^ . _:b414676400 . _:b414676841 . _:b414676842 . _:b414677876 . _:b414676843 . _:b414676844 . _:b414677198 "2"^^ . _:b414676403 . . _:b414676845 . . _:b414677879 . _:b414676846 . . _:b414676847 . _:b414676832 . _:b414677193 "2"^^ . _:b414676402 . _:b414677338 . _:b414676833 . _:b414676834 . _:b414677878 . _:b414676835 . _:b414676836 . _:b414677192 "2"^^ . _:b414676413 . _:b414676837 . . _:b414677873 . _:b414677298 . . _:b414676838 . _:b414676839 . _:b414676856 . _:b414677195 "2"^^ . _:b414676412 . _:b414676857 . _:b414676858 . _:b414677872 . _:b414676859 . _:b414676860 . _:b414677194 "2"^^ . _:b414676415 . _:b414676861 . _:b414676862 . _:b414677875 . _:b414676863 . . _:b414677818 . _:b414677205 "2"^^ . _:b414676848 . _:b414676414 . _:b414676849 . _:b414676850 . _:b414677874 . _:b414676851 . . _:b414676852 . _:b414677204 "2"^^ . _:b414676409 . _:b414676853 . _:b414676854 . _:b414677885 . _:b414676855 . _:b414676872 . _:b414677207 "2"^^ . _:b414676408 . _:b414676873 . _:b414676874 . _:b414677884 . _:b414676875 . _:b414676876 . _:b414677206 "2"^^ . _:b414676411 . _:b414676877 . _:b414676878 . _:b414677887 . _:b414677595 . _:b414676879 . _:b414677497 . _:b414676864 . _:b414677374 . _:b414677201 "2"^^ . _:b414676410 . . _:b414676865 . . _:b414676866 . _:b414677886 . _:b414676867 . _:b414676868 . _:b414677200 "2"^^ . _:b414676421 . _:b414676869 . _:b414676870 . _:b414677881 . _:b414676834 . _:b6102575 "PD-L1 is widely distributed on leukocytes, non-hematopoietic cells, and in non-lymphoid tissues including pancreatic islets, while PD-L2 is expressed exclusively on dendritic cells (DC) and monocytes 7,>>8<<. The PD-1 signaling pathway limits viral clearance during chronic infections by creating an unresponsive state in virus-specific CD8+ T cells termed \u201Cexhaustion\u201D 9. In an autoimmune setting, PD-1 is essential for maintaining T cell anergy" . _:b414676871 . _:b414676888 . _:b414677203 "2"^^ . _:b414676420 . _:b414676889 . _:b414676890 . _:b414677880 . _:b414676891 . _:b414676892 . _:b414677202 "2"^^ . _:b414676423 . _:b414676893 . _:b414676894 . _:b414677883 . . _:b414676895 . _:b414676880 . _:b414677213 "2"^^ . _:b414676422 . _:b414676881 . _:b414676882 . _:b414677882 . _:b414676883 . _:b414676884 . _:b414677212 "2"^^ . _:b414676417 . _:b414677766 . _:b414676885 . _:b414676886 . _:b414677893 . _:b414676887 . _:b414676904 . _:b414677215 "2"^^ . _:b414676441 . _:b414676416 . _:b414676905 . _:b414676906 . _:b414677892 . _:b414676344 . _:b414676907 . _:b414676572 . _:b414677444 . _:b414677214 "2"^^ . _:b414676908 . _:b414676737 . _:b414676909 . _:b414676419 . . _:b414676910 . _:b414677895 . _:b414676911 . _:b414676770 . _:b414677209 "2"^^ . _:b414676896 . _:b414676418 . _:b414676897 . _:b414676898 . _:b414677894 . _:b414676899 . _:b414676900 . _:b414677208 "2"^^ . _:b414676429 . _:b414676901 . . _:b414677889 . _:b414676902 . . . _:b414676903 . _:b414676920 . _:b414677879 . _:b414677567 . _:b414677211 "2"^^ . _:b414676428 . _:b414676921 . _:b414676922 . _:b414677888 . _:b414676923 . _:b414676924 . _:b414677210 "2"^^ . _:b414676431 . _:b414677566 . _:b414676925 . _:b414676926 . _:b414677891 . _:b414676950 . _:b414676927 . _:b414676912 . _:b414677221 "2"^^ . _:b414676430 . _:b414676913 . _:b414676914 . _:b414677890 . _:b414676915 . _:b414676916 . _:b414677220 "2"^^ . _:b414676425 . _:b414676917 . _:b414676918 . _:b414676919 . _:b414676936 . _:b414677223 "2"^^ . . _:b414676424 . _:b414676937 . _:b414676703 . _:b414676938 . . _:b414677524 . _:b414676939 . _:b414676940 . _:b414677842 . _:b414677222 "2"^^ . . _:b6102573 . _:b414676941 . _:b414676427 . _:b414676942 . _:b414676541 . _:b414676943 . _:b414676928 . _:b414677217 "2"^^ . _:b414676426 . _:b414676929 . _:b414676930 . _:b414676931 . _:b414676932 . _:b414677216 "2"^^ . _:b414676437 . _:b414676933 . . _:b414676934 . . _:b414676935 . _:b414676952 . _:b414677219 "2"^^ . _:b414676436 . _:b414676953 . _:b414676954 . _:b414677896 . _:b414676955 . . _:b414677218 "2"^^ . _:b414676956 . _:b414676439 . _:b414676957 . _:b414676958 . _:b414676607 . _:b414676959 . . _:b414676944 . _:b414677229 "2"^^ . _:b414676438 . . _:b414676945 . _:b414676946 . _:b414676947 . _:b414676948 . _:b414677228 "2"^^ . . _:b414676949 . _:b414676433 . _:b414676950 . _:b414676951 . _:b414676968 . _:b414677231 "2"^^ . _:b414676432 . _:b414676969 . _:b414676970 . _:b414676971 . _:b414676972 . _:b414677230 "2"^^ . _:b414676435 . _:b414676973 . _:b414676974 . _:b414676975 . _:b414676960 . _:b414677225 "2"^^ . _:b414676461 . _:b414676434 . _:b414676961 . _:b414676962 . _:b414676963 . _:b414676964 . _:b414677224 "2"^^ . _:b414676445 . _:b414676965 . _:b414676966 . _:b414676967 . . _:b414677227 "2"^^ . _:b414676984 . _:b414676444 . _:b414676985 . _:b414676986 . _:b414677380 . _:b414676987 . _:b414676988 . _:b414677226 "2"^^ . _:b414676447 . _:b414677792 . _:b414676989 . _:b414676990 . _:b414676991 . _:b6102571 "CTLA-4 ligation antagonizes early T cell activation leading to decreased interleukin 2 (IL-2) production, inhibition of cell cycle progression and modulation of TCR signaling 2,>>3<<. CTLA-4 and CD28 shares the ligands B7-1 (also called CD80) and B7-2 (also called CD86) 4. Mice deficient for CTLA-4 develop lymphoproliferative disease and die within 3-4 weeks of birth 5, adding further evidence for the critical role of" . _:b414676976 . _:b414677237 "2"^^ . _:b414676446 . _:b414676977 . _:b414676978 . _:b414676979 . _:b414677596 . _:b414676980 . _:b414677236 "2"^^ . _:b414676441 . _:b414676627 . _:b414676981 . _:b414676982 . _:b414676983 . _:b414676488 . _:b414677239 "2"^^ . _:b414676860 . _:b414676440 . _:b414676489 . . _:b414676490 . _:b414676491 . _:b414676492 . _:b414677238 "2"^^ . _:b414676443 . _:b6102582 . _:b414676493 . _:b414676494 . _:b414676495 . _:b414676480 . _:b414677233 "2"^^ . . _:b414676481 . _:b414676442 . _:b414676482 . _:b414676483 . _:b414676484 . _:b414677232 "2"^^ . _:b414676453 . _:b414676485 . _:b414676486 . _:b414676487 . _:b414676504 . _:b414677353 . _:b414677235 "2"^^ . _:b414676452 . _:b414676505 . . _:b6102659 "A follow-up study reported that CTLA-4-deficient T cells showed a marked resistance to a stop-signal induced by anti-CD3 >>45<<. It is difficult to explain the discrepancies between these previous studies, but it may be due to subtle differences between sorted T cell subpopulations, CTLA-4 surface stability, blocking antibodies, or use of knockout T cells. Here we" . _:b414676506 . _:b414676507 . _:b414676508 . _:b414677234 "2"^^ . _:b414676455 . _:b414676509 . _:b414676510 . _:b414676511 . _:b414676496 . _:b414677245 "2"^^ . _:b414676454 . _:b414676497 . . _:b414676498 . _:b414676499 . . _:b414676500 . _:b414677244 "2"^^ . _:b414676449 . _:b414676501 . _:b414676502 . _:b414676503 . _:b414676520 . _:b414677247 "2"^^ . . _:b414676521 . _:b414676448 . _:b414676386 . _:b414676522 . _:b414676918 . _:b414677343 . . _:b414676523 . _:b414676524 . _:b414677246 "2"^^ . . _:b414676525 . _:b414676451 . _:b414676887 . _:b414676526 . _:b414676527 . _:b414676512 . _:b414677241 "2"^^ . _:b414676450 . _:b414677825 . _:b414676513 . _:b414676514 . _:b414676515 . _:b414676516 . _:b414677240 "2"^^ . . _:b414676517 . _:b414676461 . _:b414676518 . _:b414676519 . _:b414677097 . _:b414677243 "2"^^ . _:b414676536 . _:b414676460 . _:b414676584 . _:b414676537 . _:b414676538 . _:b414676539 . _:b414676540 . _:b414677242 "2"^^ . . _:b414676463 . _:b414676541 . _:b414676542 . _:b414676543 . _:b414676528 . _:b414677253 "2"^^ . . _:b414676462 . _:b414676529 . _:b414676530 . _:b414676531 . _:b414676532 . _:b414677252 "2"^^ . _:b414676457 . . _:b414676533 . . _:b414676534 . _:b414676535 . _:b414676552 . _:b414677255 "2"^^ . _:b414676456 . _:b414676553 . _:b414676554 . _:b414676555 . _:b414676556 . _:b414677254 "2"^^ . _:b414676459 . _:b414676557 . _:b414676558 . _:b414676559 . _:b414676544 . _:b414677249 "2"^^ . _:b414676458 . _:b414676545 . _:b414676546 . _:b414676547 . _:b414676548 . _:b414677574 . _:b414677248 "2"^^ . _:b414676299 . _:b414677480 . _:b414676549 . _:b414676469 . _:b414676550 . _:b414676551 . _:b414676568 . _:b414677251 "2"^^ . . _:b414676569 . _:b414676468 . _:b414676570 . _:b414676571 . _:b414676572 . _:b414677250 "2"^^ . _:b414676471 . _:b414676573 . _:b414676574 . _:b414676575 . _:b6102626 "BDC2.5.Thy1.1.Yeti mice >>31<<. NOD.SCID mice were purchased from The Jackson Laboratory." . _:b414676560 . _:b414677261 "2"^^ . _:b414676470 . _:b414676561 . _:b414676562 . _:b414676563 . _:b414677808 . _:b414676564 . _:b414677260 "2"^^ . _:b414676465 . _:b414676565 . _:b414676566 . _:b414676567 . _:b414676584 . _:b414677263 "2"^^ . . _:b6102610 "This is likely due to the fact that tolerized T cells express high amounts of PD-1 on their surface, while na\u00EFve T cells do not 10,>>35<<. These results reinforce the notion that antigen is required for the stop signal and that PD-1 normally functions to inhibit T cell activation by preventing T cell arrest." . _:b414676585 . _:b414676464 . _:b414676586 . _:b414676587 . _:b414676588 . _:b414677262 "2"^^ . _:b414676467 . _:b414676589 . _:b414676590 . _:b414676915 . _:b414676591 . . _:b414677257 "2"^^ . _:b414676576 . _:b414676466 . _:b414676577 . _:b414676578 . _:b414676579 . _:b414676580 . _:b6102590 "As T cells migrate along the FRC highway they probe DCs for signals and antigen >>24<<. Initial interactions may be transient, but antigen recognition results in T cell swarming, formation of stable T cell-DC conjugates, and T cell arrest 25,26. TCR ligation results in \u2018stop signals\u2019 that decrease T cell motility and are" . _:b414677256 "2"^^ . _:b414676477 . _:b414676581 . _:b414676582 . . _:b414677650 . _:b414676583 . . _:b414677259 "2"^^ . _:b414676600 . . . _:b414676601 . _:b414676476 . _:b414676602 . _:b414676603 . _:b414676604 . _:b414677258 "2"^^ . _:b414676479 . _:b414676605 . _:b414676606 . _:b414676607 . _:b414676592 . _:b414677269 "2"^^ . _:b414676478 . _:b414676593 . _:b414676594 . _:b6102613 "The slope of these two curves is a straight line representing free and random walking within the target tissue and does not correspond to directed migration >>33<<. PD-L1 blockade, however, attenuated T cell motility and decreased T cell displacement when compared to isotype control antibody-treated animals (Fig. 4b, M= 0.5 \u00B1 0.3 \u03BCm2 min-1). Tracking individual cells confirmed these results (Fig." . _:b414676595 . _:b414676596 . _:b414677268 "2"^^ . _:b414676473 . _:b414676597 . _:b414676808 . _:b414676598 . _:b414676599 . _:b414676616 . _:b414677271 "2"^^ . _:b414676472 . _:b414676617 . _:b414676954 . _:b414676618 . _:b414676619 . _:b414676620 . _:b414677270 "2"^^ . _:b414676475 . . _:b414676621 . _:b414676622 . _:b414676623 . . _:b414677265 "2"^^ . _:b414676368 . _:b414676608 . _:b414676474 . _:b414676609 . _:b414676610 . _:b414677661 . _:b414677106 . _:b414676611 . _:b414676612 . _:b414677264 "2"^^ . _:b414676613 . _:b414676614 . _:b414676615 . _:b414676632 . _:b414677267 "2"^^ . _:b414676633 . _:b414676634 . _:b414676635 . _:b6102581 "Similarly, blocking PD-1-PD-L1 interactions accelerates spontaneous autoimmune diabetes 12 and reverses immune tolerance 10,>>11<<. Together these data support a central role for PD-1 as a major inhibitory pathway controlling immunity and suggest that exhaustion and peripheral tolerance are linked mechanistically." . _:b414676636 . _:b414677266 "2"^^ . _:b414676637 . _:b414676638 . _:b414676639 . _:b414676624 . _:b414677277 "2"^^ . _:b414676625 . _:b414676626 . _:b414676627 . _:b414676628 . _:b414677276 "2"^^ . _:b414676629 . _:b414676630 . . _:b414676631 . . _:b414677279 "2"^^ . _:b414676648 . _:b414676649 . _:b414676650 . _:b414676651 . _:b414676652 . _:b414677278 "2"^^ . _:b414676653 . _:b414676654 . _:b414676655 . _:b414676640 . _:b414677273 "2"^^ . _:b414676641 . _:b414676642 . _:b414676643 . _:b414677540 . . _:b414677554 . _:b414677272 "2"^^ . _:b414676644 . _:b414676645 . . _:b414676646 . _:b414676647 . _:b414676664 . _:b414677275 "2"^^ . _:b414676665 . _:b414676666 . . _:b414676667 . . _:b414677274 "2"^^ . _:b414676668 . _:b414676669 . _:b414677459 . _:b414676670 . _:b414676671 . _:b414676656 . _:b414677285 "2"^^ . _:b414676657 . . _:b414676658 . _:b414676659 . _:b414676660 . _:b414677284 "2"^^ . _:b414676661 . _:b414676662 . . _:b414676663 . _:b414676680 . _:b414677287 "2"^^ . _:b414676702 . _:b414676681 . _:b414676682 . _:b414676683 . _:b414676684 . _:b414677286 "2"^^ . _:b414677259 . . _:b414676685 . _:b414676686 . _:b414676687 . _:b414676672 . _:b414677281 "2"^^ . _:b414676564 . _:b414676673 . _:b414676674 . _:b414676675 . _:b414676676 . _:b414677280 "2"^^ . _:b414676677 . _:b414677751 . _:b414676678 . _:b414676679 . _:b414676696 . _:b414677283 "2"^^ . _:b414676697 . _:b414676698 . _:b414676699 . _:b414676700 . _:b414677282 "2"^^ . _:b414676455 . _:b414676701 . _:b414676702 . _:b414676703 . _:b414677425 . _:b414676705 . _:b414677293 "2"^^ . _:b414676688 . _:b414676689 . _:b414676690 . _:b414676691 . _:b414676692 . _:b414677292 "2"^^ . _:b414676693 . _:b414676694 . . _:b414676695 . _:b414676712 . _:b414677295 "2"^^ . . _:b414676713 . _:b414676714 . _:b414676715 . _:b414677886 . . _:b414676716 . _:b414677294 "2"^^ . _:b414677288 . _:b414676552 . _:b414676717 . _:b414676718 . _:b414676677 . _:b414676719 . _:b414676704 . _:b414677289 "2"^^ . _:b414676705 . _:b414676706 . _:b414676707 . _:b414676708 . _:b414677288 "2"^^ . _:b414676709 . _:b414677606 . _:b414676710 . _:b414676711 . _:b414676728 . _:b414677291 "2"^^ . _:b414676729 . _:b414676730 . _:b414676731 . _:b414676732 . _:b414677290 "2"^^ . _:b414676733 . _:b414676734 . . _:b414676735 . . _:b414677301 "2"^^ . _:b414676720 . _:b414676721 . _:b414676722 . _:b414676723 . _:b414677597 . _:b414676724 . _:b414677300 "2"^^ . . _:b414676725 . . _:b414676726 . _:b414676727 . _:b414677677 . . _:b414677303 "2"^^ . _:b414677256 . _:b414677257 . _:b414677258 . . _:b414677259 . . _:b414677302 "2"^^ . _:b414677260 . _:b414677261 . _:b414677262 . _:b414677263 . _:b414677248 . _:b414677803 . _:b414677297 "2"^^ . _:b414676786 . _:b414677249 . _:b414677250 . _:b414677251 . _:b414677252 . _:b414677296 "2"^^ . . _:b414677253 . _:b414677254 . _:b414677255 . _:b414677272 . _:b6102658 "One study found that CTLA-4 positive T cells failed to stop or slow down in response to in vivo peptide challenge, and anti-CTLA-4 increased T cell motility >>44<<. A follow-up study reported that CTLA-4-deficient T cells showed a marked resistance to a stop-signal induced by anti-CD3 45. It is difficult to explain the discrepancies between these previous studies, but it may be due to subtle" . _:b414677299 "2"^^ . _:b414677273 . _:b414677274 . . _:b414677275 . _:b414677276 . _:b414677298 "2"^^ . _:b414677277 . _:b414677278 . _:b414677309 . _:b414677279 . _:b414677264 . _:b414677309 "2"^^ . _:b414677265 . _:b414677266 . _:b414677267 . _:b414677268 . _:b414677308 "2"^^ . . _:b414677269 . _:b414677270 . _:b414677271 . _:b414677288 . _:b414677334 . _:b414677311 "2"^^ . _:b414677289 . _:b414677290 . . _:b414677291 . _:b414676403 . _:b414677292 . _:b414677310 "2"^^ . _:b414676596 . _:b414677293 . _:b414677294 . . _:b414677295 . _:b414677280 . _:b414677305 "2"^^ . _:b414677281 . _:b414677282 . _:b414677684 . _:b414677283 . _:b414677284 . _:b414677304 "2"^^ . . _:b414677285 . _:b6102567 "introduction" . _:b414677286 . _:b414676438 . _:b414677287 . _:b414677304 . _:b414677307 "2"^^ . . _:b414677305 . _:b414677306 . _:b414677307 . _:b414677131 . _:b414677601 . _:b414677306 "2"^^ . _:b414677240 . _:b414677308 . _:b414677309 . _:b414677310 . _:b414677311 . _:b414677296 . _:b414677317 "2"^^ . _:b414677297 . _:b414677237 . _:b414677298 . _:b414676700 . _:b414677299 . _:b414677300 . _:b414677609 . _:b414677316 "2"^^ . _:b414677301 . _:b414677302 . _:b414677303 . _:b414677320 . _:b414677319 "2"^^ . _:b414677321 . _:b414677322 . _:b414677323 . _:b414677324 . _:b414677318 "2"^^ . _:b414677325 . _:b414677326 . _:b414677327 . _:b414677312 . _:b414677313 "2"^^ . _:b414677313 . _:b414677314 . _:b414677315 . _:b414677316 . _:b414677312 "2"^^ . . _:b414677317 . _:b414677318 . . _:b414677319 . _:b414677336 . _:b414677315 "2"^^ . . _:b414677337 . _:b414677338 . _:b414677339 . . _:b414677314 "2"^^ . _:b414677340 . _:b414677341 . _:b414677342 . _:b414677343 . _:b414677328 . _:b414677325 "2"^^ . . _:b414676933 . _:b414677329 . _:b414677330 . _:b414677331 . _:b414677332 . _:b414677324 "2"^^ . _:b414677333 . _:b414677869 . . _:b414677334 . . _:b414677335 . _:b414677352 . _:b414677327 "2"^^ . . _:b414677353 . _:b414677354 . _:b414677355 . _:b414677356 . _:b414677326 "2"^^ . _:b414677357 . _:b414677358 . _:b414677359 . _:b414677344 . _:b414677321 "2"^^ . _:b414677345 . _:b414677346 . _:b414677347 . . _:b414677320 "2"^^ . _:b414677348 . _:b414677349 . _:b414677350 . _:b414677351 . _:b414677368 . _:b414677323 "2"^^ . _:b414677369 . _:b414677370 . _:b414677371 . . _:b414677372 . _:b414677322 "2"^^ . _:b414677373 . _:b414677374 . . _:b6102576 . _:b414677257 . _:b414677375 . _:b414676667 . _:b414677333 "2"^^ . _:b414677360 . _:b414677361 . _:b414676904 . _:b414677362 . _:b414677363 . _:b414677364 . _:b414677611 . _:b414677332 "2"^^ . _:b414677365 . _:b414677069 . _:b414677366 . _:b414676589 . _:b414677367 . _:b414677384 . _:b414677335 "2"^^ . _:b414677385 . _:b414677386 . _:b414677387 . . _:b414677388 . _:b414677334 "2"^^ . _:b414677389 . _:b414677390 . _:b414677391 . _:b414677376 . _:b414677329 "2"^^ . _:b414677377 . _:b414677378 . _:b414677379 . _:b414677380 . _:b414677328 "2"^^ . _:b414677381 . _:b414677382 . _:b414677383 . _:b414677400 . _:b414677331 "2"^^ . _:b414677401 . _:b414677402 . _:b414677009 . _:b414677403 . _:b414677404 . _:b414677720 . _:b414677330 "2"^^ . _:b414677405 . . _:b414677406 . _:b414677103 . _:b414677407 . _:b414677392 . _:b414677341 "2"^^ . _:b414677393 . _:b414677394 . _:b414677395 . _:b414677396 . _:b414677340 "2"^^ . _:b414677397 . _:b414677398 . _:b414677509 . _:b414677399 . _:b414677192 . _:b414677416 . _:b414677343 "2"^^ . _:b414677417 . _:b414677418 . _:b414677508 . _:b414677419 . _:b414677420 . _:b414677342 "2"^^ . _:b414677421 . _:b414677422 . _:b414677511 . _:b414677423 . _:b414677408 . _:b414677337 "2"^^ . _:b414677409 . _:b414677852 . . _:b414677510 . _:b414677410 . _:b414677411 . _:b414677083 . _:b414677336 "2"^^ . _:b414677412 . . _:b414677413 . _:b414677414 . _:b414677505 . _:b414676763 . _:b414677415 . _:b414677432 . _:b414677339 "2"^^ . . . _:b414677433 . _:b414677434 . _:b414677504 . . _:b414677435 . _:b414677436 . _:b414677338 "2"^^ . _:b414677437 . _:b414677438 . _:b414677507 . _:b414677439 . _:b414676811 . _:b414677349 "2"^^ . _:b414677424 . _:b414677425 . . _:b414677426 . _:b414677506 . _:b414677427 . _:b414677428 . _:b414677348 "2"^^ . _:b414677429 . _:b414677430 . _:b414677517 . _:b414677431 . _:b414677448 . _:b414677351 "2"^^ . _:b414677449 . _:b6102637 . _:b414677450 . _:b414677516 . _:b414677451 . . _:b414677350 "2"^^ . _:b414677452 . . _:b414677453 . _:b414677454 . _:b414677519 . . _:b414677455 . _:b414677440 . _:b414677345 "2"^^ . _:b414677441 . _:b414677442 . _:b414677518 . _:b414677443 . _:b414676998 . _:b414677444 . _:b414677344 "2"^^ . _:b414677445 . . _:b414677446 . _:b414677513 . . _:b414677447 . . _:b414677347 "2"^^ . _:b414677464 . _:b414677465 . . _:b414677512 . _:b414677466 . _:b414677467 . _:b414677468 . _:b414677346 "2"^^ . . _:b414677469 . _:b414676732 . _:b414677515 . _:b414677470 . _:b414677471 . _:b414676739 . _:b414677357 "2"^^ . _:b414677456 . _:b414677457 . _:b414677458 . _:b414677514 . _:b414676798 . _:b414677459 . _:b414677460 . _:b414677356 "2"^^ . _:b414677461 . _:b414677462 . _:b414677525 . _:b414677463 . _:b414676545 . _:b414677359 "2"^^ . _:b414677480 . _:b414677481 . _:b414677482 . _:b414677524 . _:b414677483 . _:b414677484 . _:b414677358 "2"^^ . _:b414677124 . _:b414677485 . _:b414677486 . _:b414677527 . _:b414677487 . _:b414677472 . _:b414677353 "2"^^ . _:b414677473 . _:b414677474 . _:b414677526 . _:b414677475 . _:b414677476 . _:b414677352 "2"^^ . _:b414677477 . _:b6102640 . _:b414677478 . _:b414677521 . _:b414677479 . _:b414677496 . _:b414677355 "2"^^ . _:b414676554 . _:b414677497 . _:b414677498 . _:b414677520 . . _:b414677499 . . _:b414677500 . _:b414677354 "2"^^ . _:b414677501 . _:b414677502 . _:b414677523 . _:b414677503 . _:b414677488 . _:b414677365 "2"^^ . _:b414677489 . _:b414676870 . _:b414677490 . _:b414677522 . _:b414677491 . _:b414677492 . _:b414677364 "2"^^ . _:b414677493 . _:b414677494 . _:b414677533 . _:b414677495 . _:b414677000 . _:b414677367 "2"^^ . _:b414677001 . _:b414677002 . _:b414677532 . _:b414677003 . _:b414677004 . _:b414677366 "2"^^ . _:b414677005 . _:b414677864 . . _:b414677535 . _:b414677006 . _:b414677007 . _:b414676992 . _:b414677361 "2"^^ . _:b414676993 . _:b414676994 . _:b414677534 . _:b414676995 . . _:b414677360 "2"^^ . _:b414676996 . _:b414676997 . _:b414676998 . _:b414677529 . _:b414676999 . _:b414677016 . _:b414677363 "2"^^ . _:b414677017 . _:b414677018 . _:b414677528 . _:b414676433 . _:b414677019 . _:b414677020 . _:b414677362 "2"^^ . _:b414677021 . _:b414677022 . _:b414677531 . _:b414677023 . . _:b414677373 "2"^^ . _:b414677008 . _:b414676871 . . _:b414677009 . _:b414677010 . _:b414677530 . _:b414677011 . _:b414677012 . _:b414677372 "2"^^ . . _:b414677283 . _:b414677013 . _:b414677014 . _:b414677541 . _:b414677015 . _:b414676865 . _:b414677375 "2"^^ . _:b414677032 . _:b414677033 . _:b414677034 . _:b414677540 . . _:b414677035 . _:b414677036 . _:b414677374 "2"^^ . _:b414677037 . _:b414677038 . _:b414677543 . _:b414677039 . _:b6102632 . _:b414677024 . _:b414677572 . _:b414677369 "2"^^ . _:b414677025 . . _:b414677026 . _:b414677542 . _:b414677027 . . _:b414677028 . _:b414677368 "2"^^ . _:b414677029 . _:b414677030 . _:b414677537 . _:b414677031 . _:b414677048 . _:b414677371 "2"^^ . _:b414677049 . _:b414677050 . _:b414677536 . _:b414677051 . _:b414676628 . _:b414677052 . _:b414677370 "2"^^ . _:b414677053 . _:b414677054 . _:b414677539 . _:b414677055 . _:b414677040 . _:b414677381 "2"^^ . _:b414677041 . _:b414677042 . _:b414677538 . _:b414677043 . _:b414677044 . _:b414677380 "2"^^ . _:b414677045 . _:b414677121 . _:b414677549 . _:b414677046 . _:b414677047 . _:b414677064 . _:b414677383 "2"^^ . _:b414677065 . _:b414677066 . _:b414677548 . _:b414677067 . _:b414677068 . _:b414677382 "2"^^ . _:b414676307 . _:b414677069 . _:b414677070 . _:b414677551 . _:b414677071 . _:b414677056 . _:b414677377 "2"^^ . _:b414677057 . _:b414677058 . _:b414677550 . _:b414677059 . _:b414677060 . _:b414677376 "2"^^ . _:b414677061 . _:b414677062 . _:b414677545 . _:b414677063 . _:b414676571 . _:b414677379 "2"^^ . _:b414677080 . _:b414677081 . _:b414677082 . _:b414677544 . _:b414677083 . _:b414677084 . _:b414677378 "2"^^ . _:b414677085 . _:b414676530 . . _:b414677547 . _:b414677086 . _:b414677087 . _:b414677072 . _:b414677389 "2"^^ . . _:b414677073 . _:b414677074 . _:b414677546 . . _:b6102629 . _:b414677075 . _:b414677076 . _:b414677388 "2"^^ . _:b414677077 . . _:b414676910 . _:b414677078 . _:b414677557 . _:b414677079 . _:b414677096 . _:b414677391 "2"^^ . _:b414677097 . _:b414677098 . _:b414677556 . . _:b414677122 . _:b6102631 . _:b414677099 . _:b414677100 . _:b414677390 "2"^^ . _:b414677101 . _:b414677582 . _:b414676689 . _:b414677559 . _:b414677212 . _:b414677102 . _:b414677103 . _:b6102648 . _:b414677088 . _:b414677385 "2"^^ . _:b414677089 . _:b414677090 . _:b414677558 . _:b414677091 . _:b6102649 . _:b414677092 . _:b414677384 "2"^^ . _:b414677093 . . _:b414677553 . _:b414677094 . _:b414677095 . _:b414677112 . _:b414677780 . _:b414677387 "2"^^ . . _:b414677113 . _:b414677114 . _:b414677552 . . _:b414677115 . . _:b414677386 "2"^^ . _:b414677116 . . _:b414677117 . . _:b414677555 . _:b414677118 . _:b414677119 . _:b414677104 . _:b414677397 "2"^^ . _:b414677105 . _:b414677106 . _:b414677554 . _:b414677107 . _:b414677712 . _:b414677108 . _:b414677396 "2"^^ . _:b414677109 . . _:b414677110 . _:b414677565 . _:b414677111 . _:b414677128 . _:b414677399 "2"^^ . _:b414677129 . _:b414677130 . _:b414677731 . _:b414677564 . _:b414677131 . _:b414677132 . _:b6102633 . _:b414677846 . _:b414677398 "2"^^ . _:b414677133 . _:b414676912 . _:b414677567 . _:b414677134 . _:b414676970 . _:b414677135 . . _:b414677120 . _:b414677393 "2"^^ . _:b414677121 . _:b414677122 . _:b414677566 . _:b414677123 . _:b414677124 . _:b414677392 "2"^^ . _:b414677125 . _:b414677126 . _:b414677561 . _:b414677127 . _:b414677144 . _:b414677395 "2"^^ . _:b414677145 . _:b414677146 . _:b414677560 . _:b414676671 . _:b414677147 . _:b414677148 . _:b414677394 "2"^^ . _:b414676794 . _:b414677149 . _:b414677150 . _:b414677727 . _:b414677563 . _:b414677151 . _:b414677136 . _:b414677405 "2"^^ . _:b414677137 . _:b414677138 . _:b414677562 . _:b414677139 . _:b414677494 . _:b414677140 . _:b414677533 . _:b414677404 "2"^^ . _:b414677141 . _:b414677142 . _:b414677573 . _:b414677143 . _:b414677160 . _:b414677407 "2"^^ . _:b414677161 . _:b414677162 . _:b414677572 . _:b414676636 . _:b414677163 . _:b6102649 "It is important to note that the same dose of blocking CTLA-4\u2013specific antibody was used in these MPLSM experiments as in a previous study that documented a critical role for CTLA-4 during the induction of tolerance >>10<<. We detected no influence of CTLA-4 in the migratory behavior of tolerized T cells. Due to the complex nature of lattice formation with B7-1, we have also explored anti-CTLA-4 Fab fragments with similar results as shown using intact" . _:b414677164 . _:b414677406 "2"^^ . _:b414677165 . _:b414677166 . _:b414677575 . _:b414677167 . _:b414677152 . _:b414677401 "2"^^ . _:b414677153 . _:b414677154 . _:b414677574 . _:b414677155 . . _:b414677400 "2"^^ . . _:b414677156 . _:b414677157 . _:b414677158 . _:b414677569 . _:b414677159 . _:b414677176 . _:b414677403 "2"^^ . _:b414677177 . _:b414677178 . _:b414677568 . . _:b414677179 . _:b414677180 . _:b414677402 "2"^^ . _:b414677181 . _:b414677182 . _:b414677571 . _:b414676407 . . _:b414677183 . _:b414677168 . _:b414677413 "2"^^ . . _:b414677169 . _:b414677170 . _:b414677570 . . _:b6102605 . _:b414677171 . _:b414677172 . _:b414677412 "2"^^ . . _:b414677173 . _:b414677174 . _:b414677581 . _:b414677175 . _:b414677192 . _:b414677415 "2"^^ . _:b414677193 . _:b414677456 . _:b414677194 . _:b414677580 . _:b414677195 . _:b414677196 . _:b414677414 "2"^^ . _:b414677197 . _:b414677198 . _:b414677583 . _:b414677199 . . _:b414677184 . _:b414677409 "2"^^ . _:b414677185 . _:b414677186 . _:b414677582 . _:b414677187 . _:b414677188 . _:b414677408 "2"^^ . _:b414677189 . _:b414677190 . _:b414677577 . _:b414677191 . _:b414677208 . _:b414677411 "2"^^ . _:b414677209 . _:b414677210 . _:b414677722 . _:b414677576 . _:b414677211 . _:b414677212 . _:b414677410 "2"^^ . _:b414677213 . _:b414677214 . _:b414677579 . _:b414677215 . _:b414677200 . _:b414677421 "2"^^ . _:b414677201 . _:b414677202 . _:b414677841 . _:b414677578 . _:b414677203 . _:b6102597 . _:b414677204 . _:b414677420 "2"^^ . _:b414677205 . _:b414677206 . _:b414677589 . _:b414677207 . _:b6102598 . _:b414677224 . _:b414677423 "2"^^ . _:b414677225 . _:b414677226 . _:b414677588 . _:b414677227 . _:b414677228 . _:b414677422 "2"^^ . _:b414677229 . _:b414677173 . _:b6102602 "This CD11c-YFP mouse allowed tracking of the in vivo movements of CD11c+ DC >>32<<. The velocity and displacement of control and tolerized T cells in islet antigen-bearing PLN 18-24 hours following T cell transfer was compared." . _:b414677591 . _:b414677230 . _:b414677231 . _:b6102616 . . _:b414677417 "2"^^ . _:b414677216 . _:b414677217 . _:b414677218 . _:b6102591 "Initial interactions may be transient, but antigen recognition results in T cell swarming, formation of stable T cell-DC conjugates, and T cell arrest >>25<<,26. TCR ligation results in \u2018stop signals\u2019 that decrease T cell motility and are required for stable T cell-DC conjugate formation and development of the immunological synapse 21,26. Prolonged T cell-DC interactions are critical for full" . _:b414677590 . _:b414677219 . _:b414677723 . _:b414677220 . _:b414677416 "2"^^ . _:b414677221 . _:b414677222 . _:b414677585 . _:b414677223 . _:b414677240 . _:b414677419 "2"^^ . _:b414677241 . _:b414677242 . _:b414677584 . _:b414677243 . _:b6102619 . _:b414677244 . _:b414677418 "2"^^ . _:b414677245 . _:b414677246 . _:b414677587 . _:b414677247 . _:b414677035 . _:b414677429 "2"^^ . _:b414677232 . . _:b414677233 . _:b414677234 . _:b414677586 . _:b414677235 . _:b414676958 . _:b414677428 "2"^^ . _:b414677236 . _:b414677237 . _:b6102588 . _:b414677238 . _:b414677603 . _:b414677597 . _:b414677239 . _:b414677768 . _:b414677431 "2"^^ . . _:b414677769 . . _:b414677596 . _:b414677770 . _:b414677771 . _:b6102583 . _:b414677464 . _:b414677772 . _:b414677430 "2"^^ . . _:b414677682 . _:b414677773 . . _:b414677599 . _:b414677774 . _:b414677084 . _:b414677775 . _:b414677760 . _:b414677425 "2"^^ . . _:b414677761 . _:b414676692 . _:b414677598 . _:b414677762 . . _:b6102609 . _:b414677221 . _:b414677763 . _:b414677764 . _:b414677424 "2"^^ . . _:b414677765 . . . _:b414677593 . _:b414677766 . _:b414677767 . . _:b414677784 . _:b414677427 "2"^^ . _:b414677785 . _:b414677786 . _:b414677592 . _:b414677787 . _:b6102611 . _:b414677788 . _:b414677426 "2"^^ . . _:b414677789 . . _:b414677595 . _:b414677790 . _:b414677791 . _:b414677776 . _:b414677437 "2"^^ . . _:b414677777 . . _:b414677594 . _:b414677778 . . _:b414677779 . . _:b414677780 . _:b414677436 "2"^^ . _:b414677781 . _:b414677782 . _:b414677605 . . _:b414677783 . _:b414677800 . _:b414677439 "2"^^ . _:b414677801 . _:b414677802 . _:b414677604 . _:b414676885 . _:b414677803 . _:b414677804 . _:b414677438 "2"^^ . _:b414677805 . _:b414676606 . _:b414677607 . _:b414677806 . _:b414676408 . _:b414677807 . _:b414677792 . _:b414677433 "2"^^ . . _:b414677381 . _:b414677793 . . _:b414677606 . _:b414677794 . _:b414677795 . _:b414677796 . _:b414677432 "2"^^ . _:b414677797 . _:b414677798 . _:b414677601 . _:b414676581 . _:b414677799 . _:b414677816 . _:b414677435 "2"^^ . _:b414677817 . _:b414677818 . _:b414677600 . _:b414677819 . _:b414677820 . _:b414677434 "2"^^ . _:b414677821 . . _:b414677603 . _:b414677822 . _:b414677823 . _:b414677469 . _:b414677808 . _:b414677445 "2"^^ . _:b414676332 . _:b414677809 . _:b414677810 . _:b414677602 . . _:b414677811 . . _:b414677812 . _:b414677476 . _:b414677444 "2"^^ . _:b414677813 . _:b414677814 . _:b414677613 . _:b414677815 . _:b414677832 . _:b414677447 "2"^^ . _:b414677833 . . _:b414677834 . _:b6102570 . _:b414677612 . _:b414677835 . _:b414677836 . _:b414677446 "2"^^ . _:b414677837 . _:b414677838 . _:b414677615 . . _:b414677839 . _:b414677824 . _:b414677441 "2"^^ . _:b414677825 . _:b414677826 . _:b414677859 . _:b414677614 . _:b414677827 . _:b414677828 . _:b414677440 "2"^^ . _:b414677829 . _:b414677830 . _:b414677609 . _:b414677831 . . _:b414677443 "2"^^ . _:b414677848 . _:b414677849 . _:b414677850 . _:b414677608 . _:b414677851 . _:b414677852 . _:b414677442 "2"^^ . _:b414677853 . . _:b414677631 . _:b414677611 . _:b414677854 . _:b414677855 . _:b414676820 . _:b414677453 "2"^^ . _:b414677840 . _:b414677841 . _:b414677842 . _:b414677610 . . _:b414677843 . _:b414677844 . _:b414677452 "2"^^ . _:b414677845 . . _:b414677621 . _:b414677846 . _:b414677847 . _:b414677864 . _:b414677455 "2"^^ . . _:b414677865 . _:b414677866 . _:b414677620 . . _:b414677867 . _:b414677868 . _:b414677454 "2"^^ . _:b414677869 . _:b414677870 . _:b414677623 . _:b414677871 . _:b414677302 . _:b414676923 . _:b414677449 "2"^^ . _:b414677856 . _:b414677857 . _:b414677858 . _:b414677622 . . _:b6102585 . . _:b414677859 . _:b414677860 . _:b414677448 "2"^^ . . _:b414677861 . . . _:b414677617 . _:b414677862 . _:b414677863 . _:b6102586 . _:b414677880 . _:b414677451 "2"^^ . . _:b414677881 . _:b414677882 . _:b414677616 . _:b414677467 . _:b414677883 . _:b414677884 . _:b414677450 "2"^^ . _:b414677885 . _:b414677886 . _:b414677619 . _:b414677887 . _:b414677872 . _:b414677461 "2"^^ . _:b414677873 . _:b414677874 . _:b414677618 . _:b414676440 . _:b414677875 . _:b414676346 . _:b414677460 "2"^^ . _:b414677876 . _:b414676435 . _:b414677877 . . _:b414677629 . _:b414677878 . _:b414677013 . _:b414677879 . _:b414677896 . _:b414677463 "2"^^ . . _:b414677628 . _:b414677462 "2"^^ . _:b414677716 . _:b414677631 . _:b6102655 "CTLA-4 deficiency results in rapid multi-organ tissue inflammation and death within 3-4 weeks of age, regardless of mouse genetic background >>5<<, whereas autoimmunity in PD-1-deficient mice is slower and tissue specific in a manner dependent on genetic background 4." . _:b414677888 . _:b414677457 "2"^^ . _:b414677889 . _:b414677890 . _:b414677630 . _:b414677891 . _:b6102577 . _:b414676925 . _:b414677456 "2"^^ . _:b414677892 . _:b414677893 . _:b414677894 . _:b414677625 . . _:b414677895 . _:b414677459 "2"^^ . _:b414677624 . _:b6102628 "Anti\u2013PD-1 (RMP1-14), anti\u2013PD-L1 (MIH5, MIH6), and anti\u2013PD-L2 (TY25) were made as described previously >>7<<,10. Anti-CTLA-4 (UC4F10), and anti-CTLA-4 Fab fragments were made as described previously 1. Mice were injected intraperitoneally with 250 \u03BCg anti\u2013PD-L1, anti\u2013PD-L2, anti-B7-1, anti-PD-1, or anti-CTLA-4 as indicated." . _:b414677458 "2"^^ . . _:b414677627 . _:b6102580 . _:b414677232 . _:b414677469 "2"^^ . _:b414676316 . _:b414677626 . . . . _:b414677468 "2"^^ . . _:b414677637 . . _:b414677471 "2"^^ . _:b414677618 . _:b414677304 . _:b414677636 . _:b414677470 "2"^^ . _:b414677449 . _:b414677639 . _:b414676812 . _:b414677465 "2"^^ . _:b414676619 . _:b414677638 . . _:b414677464 "2"^^ . _:b414677633 . _:b414677467 "2"^^ . _:b414677088 . _:b414677632 . _:b414677165 . _:b414677466 "2"^^ . . _:b414677635 . _:b414677477 "2"^^ . _:b414677541 . _:b414677634 . _:b414677091 . _:b414677476 "2"^^ . _:b414677645 . _:b414677479 "2"^^ . _:b414677644 . _:b414676644 . _:b414677478 "2"^^ . . _:b414677647 . _:b414676861 . _:b414677473 "2"^^ . . _:b414677646 . _:b414677472 "2"^^ . . _:b414677641 . _:b414677475 "2"^^ . _:b414677640 . _:b6102587 "Recent imaging advances have allowed the use of multi-photon laser-scanning microscopy (MPLSM) to visualize T cells in lymph nodes (LN) and non-lymphoid tissues in vivo on the single cell level >>18<<. Several groups have described the highly dynamic movement of CD4+ and CD8+ T cells, as well as DCs during T cell priming and tolerance induction 19-23." . _:b414677474 "2"^^ . _:b414677643 . _:b414676335 . _:b414677835 . _:b414677485 "2"^^ . _:b414677642 . _:b414677484 "2"^^ . _:b414677653 . _:b414677487 "2"^^ . _:b414676818 . _:b414677652 . _:b414677486 "2"^^ . _:b6102625 . _:b414677655 . _:b414677481 "2"^^ . . _:b414677654 . _:b414677480 "2"^^ . _:b414677649 . _:b414677807 . _:b414677483 "2"^^ . _:b414677868 . _:b414677417 . _:b414677648 . _:b414677482 "2"^^ . _:b414677651 . _:b414677493 "2"^^ . _:b414677348 . _:b414676908 . _:b414677650 . _:b414677492 "2"^^ . _:b414677661 . _:b414677839 . _:b414677512 . _:b414677495 "2"^^ . . _:b414677513 . . _:b414677514 . _:b414677660 . _:b414677515 . _:b414677516 . _:b414677494 "2"^^ . _:b414677517 . _:b414677518 . _:b414677663 . _:b414677026 . _:b414677519 . _:b414677504 . _:b414677489 "2"^^ . _:b414677505 . _:b414677506 . _:b414677662 . _:b414677507 . _:b414677508 . _:b414677488 "2"^^ . . _:b414677509 . . _:b414677657 . _:b414677510 . _:b414677511 . _:b414677528 . _:b414677491 "2"^^ . _:b414677529 . _:b414677530 . _:b414677656 . _:b414677531 . _:b414677532 . _:b414677490 "2"^^ . _:b414677533 . _:b414677534 . _:b414677659 . _:b414677535 . _:b414677520 . _:b414677501 "2"^^ . _:b414677521 . _:b414677522 . _:b414677658 . _:b414677523 . . _:b414677500 "2"^^ . _:b414677524 . _:b414677525 . _:b414677526 . _:b414677669 . _:b414677527 . _:b414676593 . _:b414677503 "2"^^ . _:b414677544 . _:b414677545 . _:b414677546 . _:b414677668 . _:b414677547 . _:b414677548 . _:b414677502 "2"^^ . _:b414677290 . _:b414677549 . _:b414677708 . _:b414677550 . _:b414677671 . _:b414677551 . _:b414677536 . _:b414677497 "2"^^ . . _:b414677537 . _:b414677538 . _:b414677670 . _:b414677539 . _:b414677540 . _:b414677496 "2"^^ . _:b414677541 . _:b414677546 . . _:b414677665 . _:b414677542 . _:b414677543 . . _:b414677499 "2"^^ . _:b414677560 . . _:b414677561 . _:b414677562 . _:b414677664 . _:b414677563 . _:b414677564 . _:b414677498 "2"^^ . _:b414677565 . _:b414677566 . _:b414677667 . _:b414677567 . _:b414677552 . _:b414677553 . _:b414677554 . _:b414677666 . _:b414677033 . _:b414677555 . _:b414677556 . _:b414677557 . _:b414677558 . _:b414677677 . _:b414677559 . _:b414677576 . _:b414677577 . _:b414677578 . _:b414677676 . _:b414677579 . _:b414677580 . . _:b414677581 . . _:b414677679 . _:b414677582 . _:b414677583 . _:b414677568 . _:b414677569 . _:b414677570 . _:b414677678 . _:b414677571 . _:b414677572 . _:b414677573 . . _:b414677673 . _:b414677574 . _:b414677575 . _:b414677592 . . _:b414677593 . _:b414677594 . _:b414677672 . _:b414677595 . . _:b414677596 . _:b414677597 . _:b414677598 . _:b414677675 . . _:b414677599 . . _:b414677584 . . _:b414677585 . _:b414677586 . _:b414677674 . _:b414677587 . _:b414677588 . . _:b414677589 . _:b414677590 . _:b414677685 . _:b414677591 . _:b414676917 . _:b414677608 . _:b414676755 . _:b414677609 . _:b414677610 . _:b414677684 . _:b414677611 . _:b414677612 . _:b414677613 . _:b414677614 . _:b414677687 . _:b414677615 . _:b414677600 . _:b414677772 . _:b414677601 . _:b414677278 . _:b414677602 . _:b414677686 . _:b414677603 . _:b414677471 . . _:b414677604 . _:b414677087 . _:b414677605 . . _:b414677681 . _:b414677606 . _:b414677607 . . _:b414677624 . _:b414677625 . _:b414677626 . _:b414677680 . _:b414677627 . . _:b414677628 . _:b414677629 . _:b414677630 . _:b414677683 . _:b414677631 . _:b414677616 . _:b414677617 . _:b414677618 . _:b414677682 . _:b414677619 . . _:b414677620 . _:b414677621 . _:b414677622 . _:b414677693 . _:b414677623 . _:b414677640 . _:b414676420 . _:b414677641 . . _:b414677692 . _:b414677642 . . _:b414677643 . _:b414677414 . _:b414677644 . _:b414677645 . _:b414677646 . _:b414677695 . _:b414677647 . _:b414677136 . _:b414677632 . _:b414677633 . _:b414677634 . _:b414677694 . _:b414677635 . _:b414677636 . _:b414677637 . _:b414677638 . _:b414677689 . _:b414677639 . _:b414677656 . _:b414677657 . _:b414677658 . _:b414677688 . _:b414677659 . _:b414677660 . _:b414677661 . . _:b6102622 "Bell (University of Chicago, Chicago, IL) >>46<< and were backcrossed for more than 12 generations to NOD mice." . _:b414677691 . _:b414677662 . _:b414677663 . _:b414677648 . _:b414677649 . _:b414677650 . _:b414677690 . _:b414677217 . _:b414677651 . _:b414677652 . _:b414677542 . _:b414677653 . _:b414677654 . _:b414677701 . _:b414677655 . . _:b414677672 . _:b414677673 . _:b414677674 . _:b414677700 . . _:b414677675 . _:b414676518 . _:b414677676 . _:b414677677 . _:b414677678 . _:b414677703 . _:b414677679 . _:b414677664 . _:b414677665 . . _:b414677666 . _:b414677702 . _:b414677667 . . _:b414677668 . _:b414677669 . _:b414677670 . _:b414677697 . _:b414677671 . . _:b414677688 . _:b414677689 . _:b414677690 . _:b414677696 . _:b414677691 . _:b414677692 . _:b414677693 . _:b414676304 . _:b414677699 . _:b414677694 . _:b414677695 . . _:b414677680 . _:b414677681 . _:b414676752 . _:b414677698 . _:b414677682 . _:b414677683 . _:b414677684 . _:b414677685 . _:b414677686 . _:b414677709 . . _:b414677687 . _:b414677704 . _:b414677705 . _:b414677706 . _:b414677708 . _:b414677707 . _:b414677708 . _:b414677709 . _:b414677856 . _:b414677710 . _:b414677711 . _:b414676480 . _:b414677711 . _:b414677696 . . _:b414677697 . _:b414677698 . _:b414677710 . _:b414677699 . _:b414677700 . _:b414677701 . _:b414677614 . _:b414677702 . _:b414677705 . . _:b414677703 . . _:b414677720 . _:b414677721 . _:b414677722 . _:b414677704 . _:b414677723 . _:b414676687 . _:b414677724 . _:b414677725 . _:b414677726 . _:b414677707 . _:b414677727 . _:b414677712 . _:b414677713 . _:b414677714 . _:b414677706 . _:b414677715 . _:b414677716 . _:b414677717 . _:b414677718 . _:b414677717 . . _:b414677719 . . _:b414677736 . . _:b414677737 . _:b414677738 . _:b414677716 . _:b414677739 . _:b414677740 . _:b414677741 . _:b414677742 . _:b6102635 . _:b414677719 . _:b414677743 . _:b414677728 . _:b414677729 . _:b414677730 . _:b414677718 . _:b414677731 . _:b414677732 . _:b414677733 . _:b414677734 . _:b414677713 . _:b414677322 . _:b414677735 . _:b414677709 . . _:b414677752 . _:b414677753 . _:b414677754 . _:b414677712 . _:b414677755 . . _:b414677756 . _:b414677757 . _:b414677758 . _:b414677715 . _:b414677759 . _:b414677744 . _:b414676788 . _:b414677745 . _:b414677746 . _:b414677714 . _:b414677747 . _:b414677748 . _:b414677749 . _:b414677750 . _:b414677725 . . _:b414677751 . _:b414676946 . _:b414677724 . _:b414677849 . _:b414677727 . . . _:b414677726 . _:b414677721 . _:b414677720 . _:b414677826 . _:b414676295 . _:b414676693 . . _:b414677723 . . . _:b414677722 . . . _:b414677853 . _:b414677733 . _:b414677809 . _:b414677509 . _:b414677732 . _:b6102595 . . _:b414677735 . _:b414676711 . _:b414677734 . _:b414676577 . _:b414677729 . . . _:b414677728 . _:b414676379 . _:b414677395 . _:b414677731 . _:b414676293 . _:b414677730 . . _:b414677741 . _:b6102613 . . _:b414677740 . _:b414677743 . _:b414677742 . _:b414677021 . _:b414677737 . _:b414677736 . _:b414677739 . _:b6102607 . _:b414677593 . _:b414677738 . _:b414676417 . _:b414677749 . _:b414676873 . _:b414676322 . _:b414677748 . _:b414676751 . . _:b414677751 . . . _:b414677750 . . . . _:b414677583 . _:b414677745 . . . _:b414677744 . _:b414676494 . _:b414677747 .