Central Nervous System Stromal Cells Control Local CD8 + T Cell Responses during Virus-Induced Neuroinflammation

Cupovic, Jovana; Onder, Lucas; Gil‐Cruz, Cristina; Weiler, E; Caviezel-Firner, Sonja; Pérez-Shibayama, Christian; Rülicke, Thomas; Bechmann, Ingo; Ludewig, Burkhard

doi:10.1016/j.immuni.2015.12.022

Cited by 87 publications

(98 citation statements)

References 49 publications

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“…Elevated CCL21 mRNA was also noted in CXCL13 Ϫ/Ϫ and CXCR3 Ϫ/Ϫ mice (11,24). Following infection with the JHMV heterologous MHV-A59 strain, CCR7 ligands produced by CNS stromal cells were crucial to support recruitment and local reactivation of antiviral CD8 ϩ T cells (86). These studies indicated that CNS stromal cells generate confined microenvironments that control T cell immunity and protect the host from lethal neuroinflammatory disease.…”

Section: Discussionmentioning

confidence: 86%

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: 86%

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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“…More recently, a marked increase in the frequency of PDGFRα + PDGFRβ + Cadherin-11 + ICAM-1 + fibroblasts has also been identified within cerebral lesions of mice that develop experimental autoimmune encephalomyelitis (EAE) (64). Recently, endothelial cells and perivascular fibroblasts of the brain were shown to nucleate local CD8 + T cell responses to a neurotropic virus by expressing CCR7 ligands (65). As TLS-associated LTo-like cells are considered resident and long-lived, in comparison to the circulating and short-lived hematopoietic cells, they may hold the key to the reversibility of TLS assembly, providing an interesting therapeutic target for this process.…”

Section: Lymphoid Stromal Cell Differentiation In Slos and Tlsmentioning

confidence: 99%

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation

et al. 2016

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Tertiary lymphoid structures (TLS) are organized aggregates of lymphocytes, myeloid, and stromal cells that provide ectopic hubs for acquired immune responses. TLS share phenotypical and functional features with secondary lymphoid organs (SLO); however, they require persistent inflammatory signals to arise and are often observed at target sites of autoimmune disease, chronic infection, cancer, and organ transplantation. Over the past 10 years, important progress has been made in our understanding of the role of stromal fibroblasts in SLO development, organization, and function. A complex and stereotyped series of events regulate fibroblast differentiation from embryonic life in SLOs to lymphoid organ architecture observed in adults. In contrast, TLS-associated fibroblasts differentiate from postnatal, locally activated mesenchyme, predominantly in settings of inflammation and persistent antigen presentation. Therefore, there are critical differences in the cellular and molecular requirements that regulate SLO versus TLS development that ultimately impact on stromal and hematopoietic cell function. These differences may contribute to the pathogenic nature of TLS in the context of chronic inflammation and malignant transformation and offer a window of opportunity for therapeutic interventions in TLS associated pathologies.

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“…First, the expression of MHC molecules is limited within the CNS parenchyma. Second, the entry of adaptive immune cells into the CNS via the blood-cerebrospinal fluid (CSF) barrier, the CSF-brain barrier, and the blood-brain barrier is restricted, but immune surveillance of the CNS does take place (33,34). The clinical presentation of ZIKV-infected Ifnar1 Ϫ/Ϫ mice, along with the previously described tropism of ZIKV for neurons, suggest that CD8 ϩ T cells may migrate to CNS when virus infects the neuron cells.…”

Section: Cd8 ϩ T Cell Immune Response In Zika Virus Infectionmentioning

confidence: 99%

CD8 ⁺ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

Huang

Zhang

et al. 2017

J Virol

110

100

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Zika virus (ZIKV) infection causees neurologic complications, includingGuillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8 ϩ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8 ϩ T cell response was elicited, major histocompatibility complex class I-restricted CD8 ϩ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8 ϩ T cells was developed, and virus-specific memory CD8 ϩ T cells were generated in these mice. The CD8 ϩ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8 ϩ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection.IMPORTANCE ZIKV infection has severe clinical consequences, including GuillainBarré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8 ϩ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKVspecific CD8 ϩ T cells in vivo, which simplified the detection and evaluation of ZIKVspecific immune responses. In addition, the finding that tetramer-positive memory CD8 ϩ T cell responses were generated and that CD8 ϩ T cells can traffic to a ZIKVinfected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.KEYWORDS CD8 ϩ T cell, ZIKV, central nervous system, cross protection, immunocompetent mouse model Z ika virus (ZIKV) is a mosquito-transmitted flavivirus and a member of the Flaviviridae family of positive-stranded RNA enveloped viruses; the virus has also been found to be sexually and vertically transmitted (1). It was identified in 1947 in sentinel monkeys in Uganda (2). After its introduction into Brazil in 2015, ZIKV spread rapidly, both (i) causing a mild syndrome characterized by self-limiting fever, headache, myalgia, rash, and conjunctivitis and (ii) resulting in severe clinical consequences, including Guillain-

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Central Nervous System Stromal Cells Control Local CD8 + T Cell Responses during Virus-Induced Neuroinflammation

Cited by 87 publications

References 49 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

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation

CD8 ⁺ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

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Central Nervous System Stromal Cells Control Local CD8 + T Cell Responses during Virus-Induced Neuroinflammation

Cited by 87 publications

References 49 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

Stromal Fibroblasts in Tertiary Lymphoid Structures: A Novel Target in Chronic Inflammation

CD8 + T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

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Product

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CD8 ⁺ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection