T cells expressing an invariant V_α19-J_α33 T cell receptor α-chain (V_α19i TCR) are restricted by the nonpolymorphic major histocompatibility complex class Ib molecule MR1. Whether V_α19i T cells are involved in autoimmunity is not understood. Here we demonstrate that T cells expressing the V_α19i TCR transgene inhibited the induction and progression of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Similarly, EAE was exacerbated in MR1-deficient mice, which lack V_α19i T cells. EAE suppression was accompanied by reduced production of inflammatory mediators and increased secretion of interleukin 10. Interleukin 10 production occurred at least in part through interactions between B cells and V_α19i T cells mediated by the ICOS costimulatory molecule. These results suggest an immunoregulatory function for V_α19i T cells.