B cell-derived IL-10 suppresses inflammatory disease in Lyn-deficient mice

Lyn kinase deficient mice represent a well established genetic model of autoimmune/autoinflammatory disease that resembles systemic lupus erythematosus. We report that IL-10 plays a crucial immunosuppressive role in this model, modulating the inflammatory component of the disease caused by myeloid and T-cell activation. Double-mutant lyn −/− IL-10 −/− mice manifested severe splenomegaly and lymphadenopathy, dramatically increased proinflammatory cytokine production, and severe tissue inflammation. Single-mutant lyn −/− mice showed expansion of IL-10–producing B cells. Interestingly, WT B cells adoptively transferred into lyn −/− mice showed increased differentiation into IL-10–producing B cells that assumed a similar phenotype to endogenous lyn −/− IL-10–producing B cells, suggesting that the inflammatory environment present in lyn −/− mice induces IL-10–producing B-cell differentiation. B cells, but not T or myeloid cells, were the critical source of IL-10 able to reduce inflammation and autoimmunity in double mutant lyn −/− IL-10 −/− mice. IL-10 secretion by B cells was also crucial to sustain transcription factor Forkhead Box P3 (Foxp3) expression in regulatory T cells during disease development. These data reveal a dominant immunosuppressive function of B-cell–derived IL-10 in the Lyn-deficient model of autoimmunity, extending our current understanding of the role of IL-10 and IL-10–producing B cells in systemic lupus erythematosus.