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 peptide-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-gamma(+)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 cell-dependent, interleukin-21-expressing Vbeta4(+)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.
|Authors||Marino, E.; Tan, B.; Binge, L.; Mackay, C. R.; Grey, S. T.|
|Responsible Garvan Author|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22829452|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11339|