Anti-islet autoantibodies trigger autoimmune diabetes in the presence of an increased frequency of islet-reactive CD4 T cells

OBJECTIVE - To define cellular mechanisms by which B cells promote type 1 diabetes. RESEARCH DESIGN AND METHODS - The study measured islet-specific CD4 T cell regulation in T-cell receptor transgenic mice with elevated frequencies of CD4 T cells recognizing hen egg lysozyme (HEL) autoantigen expressed in islet β-cells and thymic epithelium under control of the insulin-gene promoter. The effects of a mutation in Roquin that dysregulates T follicular helper (Tfh) cells to promote activation and anti-islet autoantibodies were studied, as were the effects of HEL antigen-presenting B cells and passively transferred or maternally transmitted anti-islet HEL antibodies. RESULTS - Mouse anti-islet IgG antibodies - either formed as a consequence of excessive Tfh activity, maternally transmitted, or passively transferred-caused a breakdown of tolerance in isletreactive CD4+ cells and fast progression to diabetes. Progression to diabetes was ameliorated in the absence of B cells or when the B cells could not secrete islet-specific IgG. Anti-islet antibodies increased the survival of proliferating islet-reactive CD4⁺ T cells. FcgR blockade delayed and reduced the incidence of autoimmune diabetes. CONCLUSIONS - B cells can promote type 1 diabetes by secreting anti-islet autoantibodies that act in an FcγR-mediated manner to enhance the expansion of islet-reactive CD4 T cells and cooperate with inherited defects in thymic and peripheral CD4 T - cell tolerance. Cooperation between inherited variants affecting CD4 T - cell tolerance and anti-islet autoantibodies should be examined in epidemiological studies and in studies examining the efficacy of depletion.