B-cell cross-presentation of autologous antigen precipitates diabetes

For autoimmune conditions like type 1 diabetes to progress, self reactive CD8+ T cells would need to interact with peptidea-antigen cross-presented on the surface of antigen-presenting cells in a major histocompatibility complex (MHC) class I-restricted fashion. However, the mechanisms by which autoantigen is cross-presented remain to be identified. In this study, we show cross-presentation of islet-derived autoantigens by B cells. B cells engage self-reactive CD8+ T cells in the pancreatic lymph node, driving their proliferative expansion and differentiation into granzyme B+interferon-g+lysosomal-associated membrane protein 1+ effector cells. B-cell cross-presentation of insulin required proteolytic cleavage and endosomal localization and was sensitive to inhibitors of protein trafficking. Absent B-cell MHC class I, or B-cell receptor restriction to an irrelevant specificity, blunted the expansion of self-reactive CD8+ T cells, suggesting B-cell antigen capture and presentation are critical in vivo events for CD8 activation. Indeed, the singular loss of B-cell MHC class I subverted the conversion to clinical diabetes in NOD mice, despite the presence of a pool of activated, and B cella-dependent, interleukin-21-expressing Vb4+CD4+ T cells. Thus, B cells govern the transition from clinically silent insulitis to frank diabetes by cross-presenting autoantigen to self-reactive CD8+ T cells. Diabetes 61:1-13, 2012