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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.

Type Journal
Authors Marino, E.; Tan, B.; Binge, L.; Mackay, C. R.; Grey, S. T.
Responsible Garvan Author (missing name)
Publisher Name DIABETES
Published Date 2012-07-26
Published Volume 61
Published Issue 11
Published Pages 2893-905
Status Published in-print
DOI 10.2337/db12-0006
URL link to publisher's version
OpenAccess link to author's accepted manuscript version