IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis

Phares, Timothy W.; DiSano, Krista D.; Hinton, David R.; Hwang, Mi-Hyun; Zajac, Allan; Stohlman, Stephen A.; Bergmann, Cornelia C.

doi:10.1016/j.jneuroim.2013.07.019

Cited by 18 publications

(18 citation statements)

References 65 publications

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“…Although retention of both CD4 and CD8 T cells in the CNS during persistence makes them likely sources of IFN-␥, de novo recruitment of T cells cannot be excluded. In this context, it is interesting that IL-21 mRNA levels were also increased, suggesting IL-21 contributes to reinvigorating local CD8 T cell effector function (10). Together, these data suggest that persisting viral replication in the absence of protective ASC is kept in check by reemerging T cell activity.…”

Section: Discussionmentioning

confidence: 84%

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Atkinson

Bergmann

2017

J Virol

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B cell subsets with phenotypes characteristic of naive, non-isotypeswitched, memory (B mem ) cells and antibody-secreting cells (ASC) accumulate in various models of central nervous system (CNS) inflammation, including viral encephalomyelitis. During neurotropic coronavirus JHMV infection, infiltration of protective ASC occurs after T cell-mediated viral control and is preceded by accumulation of non-isotype-switched IgD ϩ and IgM ϩ B cells. However, the contribution of peripheral activation events in cervical lymph nodes (CLN) to driving humoral immune responses in the infected CNS is poorly defined. CD19, a signaling component of the B cell receptor complex, is one of multiple regulators driving B cell differentiation and germinal center (GC) formation by lowering the threshold of antigen-driven activation. JHMV-infected CD19 Ϫ/Ϫ mice were thus used to determine how CD19 affects CNS recruitment of B cell subsets. Early polyclonal ASC expansion, GC formation, and virus-specific ASC were all significantly impaired in CLN of CD19 Ϫ/Ϫ mice compared to wild-type (WT) mice, consistent with lower and unsustained virus-specific serum antibody (Ab). ASC were also significantly reduced in the CNS, resulting in increased infectious virus during persistence. Nevertheless, CD19 deficiency did not affect early CNS IgD ϩ B cell accumulation. The results support the notion that CD19-independent factors drive early B cell mobilization and recruitment to the infected CNS, while delayed accumulation of virus-specific, isotype-switched ASC requires CD19-dependent GC formation in CLN. CD19 is thus essential for both sustained serum Ab and protective local Ab within the CNS following JHMV encephalomyelitis. IMPORTANCE CD19 activation is known to promote GC formation and to sustain serum Ab responses following antigen immunization and viral infections. However, the contribution of CD19 in the context of CNS infections has not been evaluated. This study demonstrates that antiviral protective ASC in the CNS are dependent on CD19 activation and peripheral GC formation, while accumulation of early-recruited IgD ϩ B cells is CD19 independent. This indicates that IgD ϩ B cells commonly found early in the CNS do not give rise to local ASC differentiation and that only antigen-primed, peripheral GC-derived ASC infiltrate the CNS, thereby limiting potentially harmful nonspecific Ab secretion. Expanding our understanding of activation signals driving CNS migration of distinct B cell subsets during neuroinflammatory insults is critical for preventing and managing acute encephalitic infections, as well as preempting reactivation of persistent viruses during immune-suppressive therapies targeting B cells in multiple sclerosis (MS), such as rituximab and ocrelizumab.

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Section: Discussionmentioning

confidence: 84%

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Atkinson

Bergmann

2017

J Virol

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“…Moreover, a single CD4 T cell appeared to interact with multiple B cells, suggesting few CD4 T cells may imprint a large number of B cells. This notion is supported by detection of CD4 T cell derived IL-21 as well as ongoing CNS expression of CXCL13, CCL19 and CCL21 within the JHMV infected CNS (Phares et al, 2011(Phares et al, , 2013a(Phares et al, , 2014(Phares et al, , 2016. These lymphoid chemokines may facilitate proximal localization of CD4 T cells and B cells especially at meningeal or perivascular sites, which also harbor antigen presenting cells driving CD4 T cell reactivation (Kivisakk et al, 2009;Ransohoff and Engelhardt, 2012).…”

Section: Discussionmentioning

confidence: 88%

“…However, local factors can further contribute in activating and/or sustaining B cells within the CNS. Lymphoid associated factors that support B cell organization, survival, and differentiation including IL-21, BAFF, CCL19, CCL21, and CXCL13, are all expressed during viral or autoimmune associated CNS inflammation (Kowarik et al, 2012;Krumbholz et al, 2006;Lalor and Segal, 2010;Magliozzi et al, 2004;Metcalf et al, 2013;Phares et al, 2011Phares et al, , 2013aPhares et al, , 2014Phares et al, , 2016Shi et al, 2001). B cell clusters associated with lymphoid chemokines, dendritic cells, and multiple B cell phenotypes are indeed evident in the CNS during MS and spinal cord injury (SCI) (Ankeny et al, 2006;Magliozzi et al, 2004Magliozzi et al, , 2007Serafini et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Activated GL7+ B cells are maintained within the inflamed CNS in the absence of follicle formation during viral encephalomyelitis

DiSano

Stohlman

Bergmann

2017

Brain, Behavior, and Immunity

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Central nervous system (CNS) inflammation associated with viral infection and autoimmune disease results in the accumulation of B cells in various differentiation stages. However, the contribution between peripheral and CNS activation remains unclear. During gliatropic coronavirus induced encephalomyelitis, accumulation of protective antibody secreting cells is preceded by infiltration of B cells with a naïve and early differentiation phenotype (Phares et al., 2014). Investigation of the temporal dynamics of B cell activation in draining cervical lymph nodes (CLN) and the CNS revealed that peak CNS infiltration of early activated, unswitched IgD+ and IgM+ B cells coincided with polyclonal activation in CLN. By contrast, isotype-switched IgG+ B cells did not accumulate until peripheral germinal center formation. In the CNS, unswitched B cells were confined to the perivascular space and meninges, with only rare B cell clusters, while isotype-switched B cells localized to parenchymal areas. Although ectopic follicle formation was not observed, more differentiated B cell subsets within the CNS expressed the germinal center marker GL7, albeit at lower levels than CLN counterparts. During chronic infection, CNS IgDint and IgD− B cell subsets further displayed sustained markers of proliferation and CD4 T cell help, which were only transiently expressed in the CLN. A contribution of local CD4 T cell help to sustain B cell activation was supported by occasional B cells adjacent to T cells. The results suggest that accumulation of differentiated B cell subsets within the CNS is largely dictated by peripheral activation, but that local events contribute to their sustained activation independent of ectopic follicle formation.

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“…CD8 T cells are essential antiviral effectors via IFN-␥-and perforin-mediated mechanisms (23,24). CD4 T cells contribute to antiviral IFN-␥ production, promote local CD8 T cell effector function (39,40), and are the major producers of anti-inflammatory IL-10 (41). We therefore assessed how the early impairment in chemokine expression affected CNS leukocyte recruitment during JHMV infection.…”

Section: Myd88 Deficiency Results In Lethal Viral Encephalomyelitismentioning

confidence: 99%

Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis

Butchi

Kapil

Puntambekar

et al. 2015

J Virol

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IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis

Cited by 18 publications

References 65 publications

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Protective Humoral Immunity in the Central Nervous System Requires Peripheral CD19-Dependent Germinal Center Formation following Coronavirus Encephalomyelitis

Activated GL7+ B cells are maintained within the inflamed CNS in the absence of follicle formation during viral encephalomyelitis

Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis

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