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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 aut...

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Detalles Bibliográficos
Autores principales: Mariño, Eliana, Tan, Bernice, Binge, Lauren, Mackay, Charles R., Grey, Shane T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478535/
https://www.ncbi.nlm.nih.gov/pubmed/22829452
http://dx.doi.org/10.2337/db12-0006
Descripción
Sumario: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-γ(+)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 Vβ4(+)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.