Regulatory T-cells in multiple sclerosis are activated by Epstein-Barr Virus and produce IL-10 in the central nervous system

Regulatory T-cells (Tregs) maintain immune homeostasis, but antigens activating adaptive Tregs in human pathologies are ill-defined. EOMES ⁺ type-1 regulatory (EOMES ⁺ Tr1-like) T-cells had a dysregulated homeostasis in multiple sclerosis (MS), which was related to their activation in the central nervous system (CNS). EOMES ⁺ Tr1-like cells were strongly enriched in patient’s cerebrospinal fluid (CSF) and were the main IL-10-producing T-cells in the CSF. IL-10 ⁺ EOMES ⁺ Tr1-like were present in MS brain lesions, and some were found close to Epstein-Barr Virus (EBV)-infected B-cells. EOMES ⁺ Tr1-like cells and FOXP3 ⁺ Tregs produced IL-10 with EBV-derived antigens, but not with major myelin antigens. EOMES ⁺ Tr1-like cells responded selectively to the latency-associated antigen EBNA1, whereas FOXP3 ⁺ Tregs responded also to lytic antigens. EBNA1-specific EOMES ⁺ Tr1-like cells were associated with anti-EBNA1 IgG, disappeared upon therapeutic B-cell depletion and were relatively abundant in patients with the HLA-DRB1*15 risk haplotype. The aberrant anti-viral specificities of Tregs in MS could undermine their protective functions and anti-EBV immune surveillance.