title: Differential Regulation of Self-reactive CD4+T Cells in Cervical Lymph Nodes and Central Nervous System during Viral Encephalomyelitis.
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 relativein vivosuppressive 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.
authors.affiliation: Department of Neurosciences, NC-30, Lerner Research Institute, Cleveland Clinic Foundation , Cleveland, OH , USA.
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.affiliation: Department of Neurosciences, NC-30, Lerner Research Institute, Cleveland Clinic Foundation , Cleveland, OH , USA.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California , Los Angeles, CA , USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Department of Neurosciences, NC-30, Lerner Research Institute, Cleveland Clinic Foundation , Cleveland, OH , USA.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
keywords: CD4+ T cells; Foxp3+ regulatory T cells; Tr1 cells; autoimmunity; central nervous system; viral infection