Regulatory B cells(Bregs)suppress and reduce autoimmune pathology.However,given the variety of Breg subsets,the role of Bregs in the pathogenesis of type 1 diabetes is still unclear.Here,we dissect this fundamental me...Regulatory B cells(Bregs)suppress and reduce autoimmune pathology.However,given the variety of Breg subsets,the role of Bregs in the pathogenesis of type 1 diabetes is still unclear.Here,we dissect this fundamental mechanism.We show that natural protection from type 1 diabetes in nonobese diabetic(NOD)mice is associated with increased numbers of IL-10-producing B cells,while development of type 1 diabetes in NOD mice occurs in animals with compromised IL-10 production by B cells.However,B cells from diabetic mice regain IL-10 function if activated by the innate immune receptor TLR4 and can suppress insulin-specific CD8 T cells in a dendritic cell(DC)-dependent,IL-10-mediated fashion.Suppression of CD8 T cells is reliant on B-cell contact with DCs.This cell contact results in deactivation of DCs,inducing a tolerogenic state,which in turn can regulate pathogenic CD8 T cells.Our findings emphasize the importance of DC–Breg interactions during the development of type 1 diabetes.展开更多
基金This work was funded by the Medical Research Council(UK)(MR/K021141/1 to FSW)LCDR was funded by a studentship from Cnpq(Conselho Nacional de Pesquisa,Brazil,grant#245609/2012-1).
文摘Regulatory B cells(Bregs)suppress and reduce autoimmune pathology.However,given the variety of Breg subsets,the role of Bregs in the pathogenesis of type 1 diabetes is still unclear.Here,we dissect this fundamental mechanism.We show that natural protection from type 1 diabetes in nonobese diabetic(NOD)mice is associated with increased numbers of IL-10-producing B cells,while development of type 1 diabetes in NOD mice occurs in animals with compromised IL-10 production by B cells.However,B cells from diabetic mice regain IL-10 function if activated by the innate immune receptor TLR4 and can suppress insulin-specific CD8 T cells in a dendritic cell(DC)-dependent,IL-10-mediated fashion.Suppression of CD8 T cells is reliant on B-cell contact with DCs.This cell contact results in deactivation of DCs,inducing a tolerogenic state,which in turn can regulate pathogenic CD8 T cells.Our findings emphasize the importance of DC–Breg interactions during the development of type 1 diabetes.
