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PMC0
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10.1084%2Fjem.20142047
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materials and methods
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Nussenzweig (The Rockefeller University, New York, NY; Lindquist et al., >>2004<<). Actin-OFP+ and actin-TFP+ were generated at the NIH as described previously (Gossa et al., 2014).
n3:mentions
n2:15543150
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Actin-OFP+ and actin-TFP+ were generated at the NIH as described previously (Gossa et al., >>2014<<). All animal experiments were conducted in accordance with the guidelines set forth by the NIH Animal Care and Use Committee.
n3:mentions
n2:25322934
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To perform adoptive immunotherapy, 2 × 107 splenocytes containing LCMV-specific memory CD8+ and CD4+ T cells against all known epitopes in B6 mice (Masopust et al., >>2007<<; Dow et al., 2008) were injected i.
n3:mentions
n2:17151096
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To perform adoptive immunotherapy, 2 × 107 splenocytes containing LCMV-specific memory CD8+ and CD4+ T cells against all known epitopes in B6 mice (Masopust et al., 2007; Dow et al., >>2008<<) were injected i.
n3:mentions
n2:18829752
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Brain-infiltrating mononuclear cells were isolated by centrifugation on a 90/60/40% discontinuous Percoll (GE Healthcare) gradient in HBSS as described previously (Lauterbach et al., >>2006<<). Single cell suspensions from spleen were prepared by mechanical disruption through a 100-µm strainer followed by red blood cell lysis with ammonium chloride buffer (0.017 M Tris-HCl and 0.14 M NH4Cl, pH 7.2). To isolate
n3:mentions
n2:16847068
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Evans blue was extracted from tissues using N,N-dimethyl formamide (Sigma-Aldrich) as described previously (Kim et al., >>2009<<). All samples were plated in triplicate on black 96-well flat-bottom plates (Corning), and fluorescence emission was quantified using a Varioskan Flash fluorometer (620-nm excitation; 695-nm emission; Thermo Fisher Scientific).
n3:mentions
n2:19011611
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n7:Section
dc:title
results
n7:contains
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After adoptive immunotherapy, persistently infected neurons in LCMV carrier mice can be purged over a 100-d period (Oldstone et al., >>1986<<; Ahmed et al., 1987).
n3:mentions
n2:3086743
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After adoptive immunotherapy, persistently infected neurons in LCMV carrier mice can be purged over a 100-d period (Oldstone et al., 1986; Ahmed et al., >>1987<<). Because antiviral T lymphocytes with a pathogenic potential enter the CNS parenchyma within the first 1–2 wk after transfer (Lauterbach et al., 2006), we initially set out to evaluate the magnitude of CNS injury during the peak T cell
n3:mentions
n2:3682061
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Because antiviral T lymphocytes with a pathogenic potential enter the CNS parenchyma within the first 1–2 wk after transfer (Lauterbach et al., >>2006<<), we initially set out to evaluate the magnitude of CNS injury during the peak T cell infiltration period.
n3:mentions
n2:16847068
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As a positive control for BBB breakdown and cytopathology, we analyzed mice with LCMV meningitis on day 6 after infection (McGavern et al., 2002a). As expected, a marked increase in apoptosis was observed on day 6 sagittal brain sections from mice with meningitis relative to naive controls (Fig. 1 A). In contrast, no increase in apoptosis was detected on brain sections from day 9
n3:mentions
n2:12352968
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We recently demonstrated that fatal immunopathology during LCMV meningitis is caused in part by CTL-induced recruitment of pathogenic myelomonocytic cells into the CNS on day 6 after infection (Kim et al., >>2009<<). To provide an explanation for the absence of CNS pathology in immunotherapy recipients, we evaluated the composition of the immune infiltrate at day 9 (Fig.
n3:mentions
n2:19011611
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In addition, the number of traceable LCMV TCR transgenic (tg) CD8+ T cells (referred to as P14 cells; Pircher et al., >>1989<<) and CD4 T cells was also slightly elevated in the CNS of immunotherapy recipients despite the minimal pathology (Fig.
n3:mentions
n2:2573841
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Previous studies have shown that neurons are the primary cell population infected in the parenchyma of LCMV carrier mice (Kunz et al., >>2006<<; Lauterbach et al., 2006).
n3:mentions
n2:16940520
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Previous studies have shown that neurons are the primary cell population infected in the parenchyma of LCMV carrier mice (Kunz et al., 2006; Lauterbach et al., >>2006<<). However, we postulated that microglia might also contain viral antigen, allowing them to serve as APCs during the immunotherapeutic process. To address this question, we used an mAb against the LCMV nucleoprotein (NP) to flow
n3:mentions
n2:16847068
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To evaluate the spatial relationship between APCs and antiviral T cells after adoptive immunotherapy, we generated CD11c-YFP (Lindquist et al., >>2004<<) carrier mice and treated these mice with antiviral memory cells that were seeded with traceable P14 CTLs expressing OFP under the actin promoter (referred to as OFP+ P14 cells).
n3:mentions
n2:15543150
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_:vb42135265
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We published previously that host CD11c+ APCs were required for successful clearance of CNS virus after adoptive immunotherapy in carrier mice (Lauterbach et al., >>2006<<). Consistent with this conclusion, we observed a significant increase in the parenchymal distribution of CD11c+ cells 12 d after adoptive immunotherapy relative to untreated carrier controls (Fig. 3, B and C). The cells colocalized with
n3:mentions
n2:16847068
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This corresponded temporally with the arrival of antiviral T cells (Lauterbach et al., >>2006<<). We reported previously that antiviral CTLs can promote recruitment of peripherally derived CD11c+ APCs after adoptive immunotherapy (Lauterbach et al., 2006), but the ubiquitous distribution observed in the parenchyma of treated
n3:mentions
n2:16847068
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We reported previously that antiviral CTLs can promote recruitment of peripherally derived CD11c+ APCs after adoptive immunotherapy (Lauterbach et al., >>2006<<), but the ubiquitous distribution observed in the parenchyma of treated CD11c-YFP carrier mice suggested that brain-resident microglia might also become activated and function as APCs (Fig.
n3:mentions
n2:16847068
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Previous studies have used these phenotypic markers to flow cytometrically distinguish between microglia and monocytes/macrophages (Sedgwick et al., >>1991<<; Butovsky et al., 2012; D’Agostino et al., 2012), and the meninges (which are devoid of microglia) served as control for the validity of this approach (Fig.
n3:mentions
n2:1651506
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Previous studies have used these phenotypic markers to flow cytometrically distinguish between microglia and monocytes/macrophages (Sedgwick et al., 1991; Butovsky et al., >>2012<<; D’Agostino et al., 2012), and the meninges (which are devoid of microglia) served as control for the validity of this approach (Fig.
n3:mentions
n2:22863620
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Previous studies have used these phenotypic markers to flow cytometrically distinguish between microglia and monocytes/macrophages (Sedgwick et al., 1991; Butovsky et al., 2012; D’Agostino et al., >>2012<<), and the meninges (which are devoid of microglia) served as control for the validity of this approach (Fig.
n3:mentions
n2:22474352
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whether antiviral T cells interacted directly with CD11c+ microglia during adoptive immunotherapy, we performed two-photon laser-scanning microscopy (TPLSM) to study T cell–microglia interactions in living brain tissue (Herz et al., >>2012<<). We studied antiviral CD8+ and CD4+ T cell dynamics simultaneously by seeding memory donor mice with OFP+ P14 cells and TFP+ SMARTA cells.
n3:mentions
n2:22846498
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The latter are TCR-tg mice in which nearly all CD4+ T cells recognize the LCMV glycoprotein amino acids 61–80 (Oxenius et al., >>1998<<). Memory splenocytes containing OFP+ P14 cells and TFP+ SMARTA cells were adoptively transferred into CD11c-YFP+ carrier mice and examined by TPLSM on day 12 (Fig. 7). Interestingly, both traceable antiviral T cell populations interacted
n3:mentions
n2:9485218
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Previous studies have shown that IFN-γ production by antiviral T cells is required for successful viral clearance after adoptive immunotherapy (Tishon et al., >>1995<<). Therefore, we examined the brains of immunotherapy recipients for evidence of IFNγ production and downstream signaling in CD11c+ microglia. At day 12 after immunotherapy, a significant increase in IFNγ mRNA expression was observed
n3:mentions
n2:7676639
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Antiviral T cell interactions with infected APCs and neurons in brain parenchyma can give rise to immunopathology (Merkler et al., >>2006<<; Kreutzfeldt et al., 2013). Effector T cells possess lytic effector molecules like granzymes and perforin that are known to induce apoptosis (Kägi et al., 1996).
n3:mentions
n2:16604192
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Antiviral T cell interactions with infected APCs and neurons in brain parenchyma can give rise to immunopathology (Merkler et al., 2006; Kreutzfeldt et al., >>2013<<). Effector T cells possess lytic effector molecules like granzymes and perforin that are known to induce apoptosis (Kägi et al., 1996).
n3:mentions
n2:23999498
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Effector T cells possess lytic effector molecules like granzymes and perforin that are known to induce apoptosis (Kägi et al., >>1996<<). Indeed, the majority of P14 CTLs (∼65%) extracted from the brains of day 12 immunotherapy recipients expressed granzyme B, which was only modestly reduced when compared with CTLs obtained from day 6 meningitis mice (the positive control
n3:mentions
n2:8717513
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discussion
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Although antiviral T cells can promote undesirable immunopathology (Kägi et al., >>1996<<), they do possess the capacity to purge viruses noncytopathically (Guidotti et al., 1999b; Guidotti and Chisari, 2001).
n3:mentions
n2:8717513
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Although antiviral T cells can promote undesirable immunopathology (Kägi et al., 1996), they do possess the capacity to purge viruses noncytopathically (Guidotti et al., 1999b; Guidotti and Chisari, 2001).
n3:mentions
n2:10221919
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Although antiviral T cells can promote undesirable immunopathology (Kägi et al., 1996), they do possess the capacity to purge viruses noncytopathically (Guidotti et al., 1999b; Guidotti and Chisari, >>2001<<). In this study, we sought novel insights into the therapeutic removal of a persistent virus from the brain. We uncovered that microglia in addition to neurons contained LCMV in mice persistently infected from birth (LCMV carrier).
n3:mentions
n2:11244031
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Because microglia can serve as APCs (Nayak et al., >>2014<<), their infection in this model opened the possibility of CNS immunopathology after T cell engagement.
n3:mentions
n2:24471431
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Previous examination of LCMV carrier mice uncovered that neurons are a primary target of the virus (Mims, >>1966<<; Rodriguez et al., 1983; Fazakerley et al., 1991), and it was postulated that these cells were cleared in an MHC I–independent manner because of their failure to display peptide–MHC I complexes (Joly et al., 1991; Joly and Oldstone, 1992).
n3:mentions
n2:5331383
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Previous examination of LCMV carrier mice uncovered that neurons are a primary target of the virus (Mims, 1966; Rodriguez et al., >>1983<<; Fazakerley et al., 1991), and it was postulated that these cells were cleared in an MHC I–independent manner because of their failure to display peptide–MHC I complexes (Joly et al., 1991; Joly and Oldstone, 1992).
n3:mentions
n2:6336906
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Previous examination of LCMV carrier mice uncovered that neurons are a primary target of the virus (Mims, 1966; Rodriguez et al., 1983; Fazakerley et al., >>1991<<), and it was postulated that these cells were cleared in an MHC I–independent manner because of their failure to display peptide–MHC I complexes (Joly et al., 1991; Joly and Oldstone, 1992).
n3:mentions
n2:1649899
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of the virus (Mims, 1966; Rodriguez et al., 1983; Fazakerley et al., 1991), and it was postulated that these cells were cleared in an MHC I–independent manner because of their failure to display peptide–MHC I complexes (Joly et al., >>1991<<; Joly and Oldstone, 1992). Using a more sensitive approach, our experiments have revealed that neurons are not the only cell population that contains LCMV antigen in the carrier brain.
n3:mentions
n2:1891717
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Rodriguez et al., 1983; Fazakerley et al., 1991), and it was postulated that these cells were cleared in an MHC I–independent manner because of their failure to display peptide–MHC I complexes (Joly et al., 1991; Joly and Oldstone, >>1992<<). Using a more sensitive approach, our experiments have revealed that neurons are not the only cell population that contains LCMV antigen in the carrier brain.
n3:mentions
n2:1610569
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This is an important observation because microglia are known to serve as APCs in models of infection and autoimmunity (McMahon et al., >>2005<<; John et al., 2011; D’Agostino et al., 2012).
n3:mentions
n2:15735651
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This is an important observation because microglia are known to serve as APCs in models of infection and autoimmunity (McMahon et al., 2005; John et al., >>2011<<; D’Agostino et al., 2012).
n3:mentions
n2:21949652
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This is an important observation because microglia are known to serve as APCs in models of infection and autoimmunity (McMahon et al., 2005; John et al., 2011; D’Agostino et al., >>2012<<). Moreover, antiviral cytokines released at the immunological synapse between T cells and infected microglia could potentially spill over onto adjacently infected neurons, resulting in bystander clearance in an MHC I–independent manner.
n3:mentions
n2:22474352
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Studies of viral clearance in the infected liver have provided precedence for this mode of clearance (Guidotti et al., 1999a; Guidotti and Chisari, 2001).
n3:mentions
n2:10330434
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Studies of viral clearance in the infected liver have provided precedence for this mode of clearance (Guidotti et al., 1999a; Guidotti and Chisari, >>2001<<). In addition, a recent in vitro study demonstrated that IFNγ release by T cells at the immunological synapse can result in STAT1 signaling in adjacent nonengaged cells, providing support for the concept of cytokine spillover (Sanderson
n3:mentions
n2:11244031
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a recent in vitro study demonstrated that IFNγ release by T cells at the immunological synapse can result in STAT1 signaling in adjacent nonengaged cells, providing support for the concept of cytokine spillover (Sanderson et al., >>2012<<).
n3:mentions
n2:22547816
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This is exemplified in adult mice infected intracerebrally with LCMV, which induces fatal immune-mediated meningitis (McGavern et al., 2002a,b; Kim et al., 2009).
n3:mentions
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This is exemplified in adult mice infected intracerebrally with LCMV, which induces fatal immune-mediated meningitis (McGavern et al., 2002a,b; Kim et al., >>2009<<). Interestingly, carrier mice receiving adoptive immunotherapy showed no significant increase in parenchymal apoptosis or vascular leakage despite having a comparable number of brain-infiltrating CTLs to mice with meningitis. It is
n3:mentions
n2:19011611
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demonstrated previously in mice with LCMV meningitis that antiviral CD8+ T cells can promote the recruitment of innate myelomonocytic cells, which severely disrupt CNS vascular integrity through synchronous extravasation (Kim et al., >>2009<<; Kang and McGavern, 2010). CD8+ T cells accomplish this through the release of myelomonocytic cell–recruiting chemoattractants (Kim et al., 2009).
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in mice with LCMV meningitis that antiviral CD8+ T cells can promote the recruitment of innate myelomonocytic cells, which severely disrupt CNS vascular integrity through synchronous extravasation (Kim et al., 2009; Kang and McGavern, >>2010<<). CD8+ T cells accomplish this through the release of myelomonocytic cell–recruiting chemoattractants (Kim et al., 2009).
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CD8+ T cells accomplish this through the release of myelomonocytic cell–recruiting chemoattractants (Kim et al., >>2009<<). In contrast to mice with meningitis, we observed that the brains of immunotherapy recipients were completely devoid of myelomonocytic cells, and this was explained mechanistically by a narrow chemoattractant expression profile. Only two
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Acute LCMV infection induces a robust IFN-I response that is responsible for nearly all gene expression in the infected brain (Nayak et al., >>2013<<). This innate program is so important in shaping pathogenic CNS immune activity that deficiency in IFN-I signaling completely prevents fatal LCMV meningitis (Müller et al., 1994; Sandberg et al., 1994). In contrast, LCMV carrier mice have
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This innate program is so important in shaping pathogenic CNS immune activity that deficiency in IFN-I signaling completely prevents fatal LCMV meningitis (Müller et al., >>1994<<; Sandberg et al., 1994).
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This innate program is so important in shaping pathogenic CNS immune activity that deficiency in IFN-I signaling completely prevents fatal LCMV meningitis (Müller et al., 1994; Sandberg et al., >>1994<<). In contrast, LCMV carrier mice have grown up with the virus from birth and therefore have very low levels of IFN-I in circulation despite being highly viremic (Bukowski et al., 1983). Adoptive transfer of antiviral T cells into mice
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In contrast, LCMV carrier mice have grown up with the virus from birth and therefore have very low levels of IFN-I in circulation despite being highly viremic (Bukowski et al., >>1983<<). Adoptive transfer of antiviral T cells into mice with low IFN-I could favor the induction of a more tailored chemokine response driven by type 2 IFN, whereas abundant release of both IFN types in mice with acute meningitis may trigger a
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The CNS meninges and choroid plexus are inhabited by peripherally derived CD11c+ APCs that bear some resemblance to splenic DCs (Anandasabapathy et al., >>2011<<). Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., 2000; Karman et al., 2004; Lauterbach et al., 2006; John et al., 2011; D’Agostino et al., 2012). In fact, we
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Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., >>2000<<; Karman et al., 2004; Lauterbach et al., 2006; John et al., 2011; D’Agostino et al., 2012).
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Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., 2000; Karman et al., >>2004<<; Lauterbach et al., 2006; John et al., 2011; D’Agostino et al., 2012).
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Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., 2000; Karman et al., 2004; Lauterbach et al., >>2006<<; John et al., 2011; D’Agostino et al., 2012).
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Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., 2000; Karman et al., 2004; Lauterbach et al., 2006; John et al., >>2011<<; D’Agostino et al., 2012).
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Studies have also demonstrated that peripherally derived DCs can enter the brain during states of inflammation (Fischer et al., 2000; Karman et al., 2004; Lauterbach et al., 2006; John et al., 2011; D’Agostino et al., >>2012<<). In fact, we showed previously that successful viral clearance after adoptive immunotherapy in LCMV carrier mice requires T cell–DC interactions (Lauterbach et al., 2006). However, DCs are not the only APCs that express CD11c+. Microglia
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In fact, we showed previously that successful viral clearance after adoptive immunotherapy in LCMV carrier mice requires T cell–DC interactions (Lauterbach et al., >>2006<<). However, DCs are not the only APCs that express CD11c+. Microglia have been shown to up-regulate CD11c after activation both in vitro (Santambrogio et al., 2001) and in vivo (Bulloch et al., 2008). Consistent with this potential, we
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Microglia have been shown to up-regulate CD11c after activation both in vitro (Santambrogio et al., >>2001<<) and in vivo (Bulloch et al., 2008).
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Microglia have been shown to up-regulate CD11c after activation both in vitro (Santambrogio et al., 2001) and in vivo (Bulloch et al., >>2008<<). Consistent with this potential, we observed that therapeutic antiviral T cells induced most brain-resident microglia to up-regulate CD11c, proliferate, and convert into APCs with the enhanced ability to present antigen and produce T
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The mechanism of microglia activation after antiviral T cell infiltration was dependent in part on T cell–derived IFNγ, a cytokine required for successful viral clearance in immunotherapy recipients (Tishon et al., >>1995<<). Evidence of downstream signaling (pSTAT1) was detected in parenchymal CD11c+ microglia, which is consistent with the link between STAT1 signaling and CD11c expression revealed in our pathway analysis of the microarray data.
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This is consistent with a previous study showing that stereotactic injection of IFNγ into the brain induced up-regulation of MHC II on CD11c+ microglia (Gottfried-Blackmore et al., >>2009<<). Microglia activation may also depend on other cytokines like GM-CSF. For example, microglia stimulated in vitro with GM-CSF were shown to up-regulate CD11c+ and acquire a DC-like phenotype (Santambrogio et al., 2001), and pathway
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For example, microglia stimulated in vitro with GM-CSF were shown to up-regulate CD11c+ and acquire a DC-like phenotype (Santambrogio et al., >>2001<<), and pathway analysis revealed evidence of GM-CSF signaling in microglia after immunotherapy (Table S2).
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Low peptide–MHC II in the presence of chemokine release may override the TCR-induced stop signal in CD4+ T cells, fostering an association with microglia but not full arrest (Bromley et al., >>2000<<). It has nevertheless been shown that even short-duration interactions like these can result in T cell signaling (Friedman et al., 2010). Even more interesting is the fact that despite stable engagement by antiviral CTLs, microglia were
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It has nevertheless been shown that even short-duration interactions like these can result in T cell signaling (Friedman et al., >>2010<<). Even more interesting is the fact that despite stable engagement by antiviral CTLs, microglia were purged of virus without evidence of apoptosis. In fact, our microarray and BrdU studies demonstrated that immunotherapy induced
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A previous study demonstrated that CTLs can achieve noncytolytic clearance of HSV-1–infected sensory neurons via granzyme B–mediated degradation of an essential viral protein (Knickelbein et al., >>2008<<). Antiviral cytokines such as IFNγ and TNF have also been shown to facilitate noncytopathic viral clearance (Guidotti and Chisari, 2001), and both cytokines are required for the resolution of a persistent LCMV infection after adoptive
n3:mentions
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Antiviral cytokines such as IFNγ and TNF have also been shown to facilitate noncytopathic viral clearance (Guidotti and Chisari, >>2001<<), and both cytokines are required for the resolution of a persistent LCMV infection after adoptive immunotherapy (Tishon et al., 1995; Lauterbach et al., 2006).
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IFNγ and TNF have also been shown to facilitate noncytopathic viral clearance (Guidotti and Chisari, 2001), and both cytokines are required for the resolution of a persistent LCMV infection after adoptive immunotherapy (Tishon et al., >>1995<<; Lauterbach et al., 2006). However, it is important to emphasize that the sole reliance on noncytopathic viral clearance mechanisms is unique to the CNS in carrier mice.
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shown to facilitate noncytopathic viral clearance (Guidotti and Chisari, 2001), and both cytokines are required for the resolution of a persistent LCMV infection after adoptive immunotherapy (Tishon et al., 1995; Lauterbach et al., >>2006<<). However, it is important to emphasize that the sole reliance on noncytopathic viral clearance mechanisms is unique to the CNS in carrier mice.
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These inhibitors are used by CTLs, for example, to prevent self-inflicted injury (Zhang et al., >>2006<<), and several serine protease inhibitors were up-regulated in microglia from immunotherapy mice (Table S2).
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Another possibility is the expression of immunoregulatory molecules that uniquely shape the activity of antiviral T cells operating in the CNS parenchyma (Suvas et al., >>2006<<).
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