title: B-cell cross-presentation of autologous antigen precipitates diabetes.
abstract: 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.
authors: Immunology Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors: Eliana
authors: E
authors: Mariño
authors: Bernice
authors: B
authors: Tan
authors: Lauren
authors: L
authors: Binge
authors: Charles R
authors: CR
authors: Mackay
authors: Shane T
authors: ST
authors: Grey
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001324:Autoantigens / Q000009:adverse effects* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002678:Chimera; D018920:Coculture Techniques; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D007515:Islets of Langerhans / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010179:Pancreas / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011236:Prediabetic State / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D001324:Autoantigens