Journal Article

B-Cell Cross-Presentation of Autologous Antigen Precipitates Diabetes

Mackay, Charles R., Binge, Lauren, Grey, Shane T., Mariño, Eliana, Tan, Bernice

2012

Overview

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.

• Publisher: American Diabetes Association
• Subject: Analysis / Animals / Antigen Presentation / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - metabolism / Antigen-Presenting Cells - pathology / Autoantigens - adverse effects / Autoantigens - metabolism / B cells / B-Lymphocytes - immunology / B-Lymphocytes - metabolism / B-Lymphocytes - pathology / Biological and medical sciences / Bone Marrow Transplantation - immunology / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / CD4-Positive T-Lymphocytes - pathology / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - pathology / Cell Proliferation / Cells, Cultured / Chimera / Coculture Techniques / Development and progression / Diabetes / Diabetes mellitus / Diabetes Mellitus, Type 1 - immunology / Diabetes Mellitus, Type 1 - metabolism / Diabetes Mellitus, Type 1 - pathology / Diabetes. Impaired glucose tolerance / Disease Progression / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / Immunology and Transplantation / Islets of Langerhans - immunology / Islets of Langerhans - metabolism / Islets of Langerhans - pathology / Lymph Nodes - drug effects / Lymph Nodes - immunology / Lymph Nodes - pathology / Medical sciences / Mice / Mice, Inbred NOD / Mice, Knockout / Pancreas - immunology / Pancreas - metabolism / Pancreas - pathology / Physiological aspects / Prediabetic State - immunology / Prediabetic State - metabolism / Prediabetic State - pathology