Regulatory T-cells in multiple sclerosis produce IL-10 in the central 1 nervous system but are activated by Epstein-Barr Virus

Regulatory T-cells (Tregs) maintain immune homeostasis, but antigens activating adaptive Tregs in human pathologies are ill-defined. EOMES ⁺ type-1 regulatory (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 enriched and clonally expanded in patient’s cerebrospinal fluid (CSF) and were the major IL-10-producing T-cell subset in the CNS. Regulatory T-cells from PwMS produced IL-10 and IFN-γ with antigens derived from Epstein-Barr Virus (EBV), but not from myelin. EOMES ⁺ Tr1-like cells responded selectively to the latency-associated antigen EBNA1, whereas FOXP3 ⁺ Tregs and Th1-cells responded also to lytic EBV antigens. EBNA1-specific EOMES ⁺ Tr1-like cells were present in patients carrying the HLA-DRB1*15:01 risk allele, were associated with anti-EBNA1 IgG and disappeared upon therapeutic B-cell depletion. IL-10 ⁺ EOMES ⁺ Tr1-like were present in MS brain lesions, and some were in the vicinity of EBV-infected B-cells and CD8 ⁺ T-cells. Notably, EOMES ⁺ Tr1-like cells suppressed CD8+T-cell activation by EBV-infected B-cells. We propose that the insufficient protective functions of Tregs in MS are due to their aberrant anti-viral specificities that promote immune escape of a disease-associated virus.