Follicular regulatory T cells promote experimental autoimmune encephalomyelitis by supporting B cell egress from germinal centers

Follicular regulatory T cells (T_fr cells) constitute a subset of regulatory T cells pivotal to the immune response in germinal centers (GCs) that inhibit autoantibody production. Their role, however, remains ill-defined in autoimmune diseases like multiple sclerosis (MS) and its murine model, experimental autoimmune encephalomyelitis (EAE), which are neuroinflammatory diseases driven by T and B cells. Here, we quantified peripheral blood immune subpopulations in two cohorts of patients with MS and found higher circulating T_fr cell frequencies in patients in relapse compared with patients in remission. To examine the functional role of T_fr cells in autoimmune neuroinflammation, we used EAE mouse models and showed that Foxp3^cre/creBcl6^fl/fl T_fr cell-deficient mice developed milder EAE than wild-type (WT) mice. Flow cytometry analysis demonstrated that the reduction of encephalomyelitis in T_fr cell-deficient mice was associated with fewer B cells infiltrating the central nervous system. Coculture experiments showed that B cells isolated from brains of WT mice at the peak of the disease fostered pro-inflammatory cytokine production by myelin oligodendrocyte glycoprotein-specific T cells. We furthermore showed that sphingosine-1-phosphate receptor 2 (S1PR2) expression in GC B cells was up-regulated in T_fr cell-deficient mice. Treatment with an S1PR2 receptor antagonist abrogated the improved EAE clinical scores in T_fr cell-deficient mice, and this loss of protection was associated with increased B cell infiltration into the brain and increased pro-inflammatory cytokine production by encephalitogenic T cells. These findings demonstrate that T_fr cells contribute to autoimmune encephalomyelitis and suggest that their blood frequency reflects MS activity.