Abstract
Viral infections have long been implicated as triggers of autoimmune diseases, including multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disorder. Epitope spreading, molecular mimicry, cryptic antigen, and bystander activation have been implicated as mechanisms responsible for activating self-reactive (SR) immune cells, ultimately leading to organ-specific autoimmune disease. Taking advantage of coronavirus JHM strain of mouse hepatitis virus (JHMV)-induced demyelination, this study demonstrates that the host also mounts counteractive measures to specifically limit expansion of endogenous SR T cells. In this model, immune-mediated demyelination is associated with induction of SR T cells after viral control. However, their decline during persisting infection, despite ongoing demyelination, suggests an active control mechanism. Antigen-specific IL-10-secreting CD4+ T cells (Tr1) and Foxp3+ regulatory T cells (Tregs), both known to control autoimmunity and induced following JHMV infection, were assessed for their relative in vivo suppressive function of SR T cells. Ablation of Foxp3+ Tregs in chronically infected DEREG mice significantly increased SR CD4+ T cells within cervical lymph nodes (CLN), albeit without affecting their numbers or activation within the CNS compared to controls. In contrast, infected IL-27 receptor deficient (IL-27R−/−) mice, characterized by a drastic reduction of Tr1 cells, revealed that SR CD4+ T cells in CLN remained unchanged but were specifically increased within the CNS. These results suggest that distinct Treg subsets limit SR T cells in the draining lymph nodes and CNS to maximize suppression of SR T-cell-mediated autoimmune pathology. The JHMV model is thus valuable to decipher tissue-specific mechanisms preventing autoimmunity.
Highlights
Viruses have long been associated with autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), both as potential inducers and as facilitators of a selfreactive (SR) immune response [1, 2]
To investigate a function of Foxp3+ regulatory T cells (Tregs) during JHM strain of mouse hepatitis virus (JHMV) persistence, we infected DEREG mice, in which diphtheria toxin (DT) treatment abrogated the vast majority of Foxp3+ Tregs under homeostatic conditions but retained a minor fraction thereby circumventing lymphoproliferative disease [22]
High fluorescent intensity of enhanced green fluorescent protein (eGFP) expressed under control of the Foxp3 promoter in DEREG mice enabled a distinct separation of the Foxp3+ population among CD4+ T cells compared to direct intracellular Foxp3-staining in WT mice (Figure 1A)
Summary
Viruses have long been associated with autoimmune diseases of the central nervous system (CNS), such as multiple sclerosis (MS), both as potential inducers and as facilitators of a selfreactive (SR) immune response [1, 2]. While the detection of viral antigens and antiviral antibodies in MS brains supports a role for viral infections in triggering autoimmunity [3,4,5], the “hygiene hypothesis” rather proposes a protective function [6, 7], underlining the ambiguous link between viral infections and MS [8] This dichotomy between viral infections and autoimmune diseases is reflected in two prominent models of viral-induced demyelination, i.e., Theiler’s murine encephalomyelitis virus (TMEV) and neurotropic mouse hepatitis virus (MHV). The endogenous SR T cell response declined despite sustained myelin loss during viral persistence and the preserved ability of antigen-presenting cells from both cervical lymph nodes (CLN) and the CNS to activate myelin-specific CD4+ T cells ex vivo These findings suggested that chronic JHMV infection actively induces suppressive mechanisms to limit the development of autoimmunity
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