Tim-1 is essential for induction and maintenance of IL-10 in regulatory B cells and their regulation of tissue inflammation

T cell Ig and mucin domain (Tim)-1 identifies IL-10–producing regulatory B cells (Bregs). Mice on the C57BL/6 background harboring a loss-of-function Tim-1 mutant showed progressive loss of IL-10 production in B cells and with age developed severe multiorgan tissue inflammation. We demonstrate that Tim-1 expression and signaling in Bregs are required for optimal production of IL-10. B cells with Tim-1 defects have impaired IL-10 production but increased proinflammatory cytokine production, including IL-1 and IL-6. Tim-1–deficient B cells promote Th1 and Th17 responses but inhibit the generation of regulatory T cells (Foxp3+ and IL-10–producing type 1 regulatory T cells) and enhance the severity of experimental autoimmune encephalomyelitis. Mechanistically, Tim-1 on Bregs is required for apoptotic cell (AC) binding to Bregs and for AC-induced IL-10 production in Bregs. Treatment with ACs reduces the severity of experimental autoimmune encephalomyelitis in hosts with wild-type but not Tim-1–deficient Bregs. Collectively, these findings suggest that in addition to serving as a marker for identifying IL-10–producing Bregs, Tim-1 is also critical for maintaining self-tolerance by regulating IL-10 production in Bregs.