B-Cell Cross-Presentation of Autologous Antigen Precipitates Diabetes
| Autor: | Charles R. Mackay, Bernice Tan, Eliana Mariño, Shane T. Grey, Lauren C. Binge |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
CD4-Positive T-Lymphocytes
Endocrinology Diabetes and Metabolism Antigen presentation CD1 Antigen-Presenting Cells CD8-Positive T-Lymphocytes Autoantigens Prediabetic State Islets of Langerhans Mice Mice Inbred NOD MHC class I Internal Medicine Cytotoxic T cell Animals Antigen-presenting cell Pancreas Cells Cultured Bone Marrow Transplantation Cell Proliferation Mice Knockout Antigen Presentation B-Lymphocytes CD40 biology Chimera Cross-presentation MHC restriction Coculture Techniques Cell biology Diabetes Mellitus Type 1 Immunology biology.protein Disease Progression Female Lymph Nodes Immunology and Transplantation |
| Zdroj: | Diabetes |
| ISSN: | 1939-327X 0012-1797 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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