Identification of autoreactive CD8+ T cell responses targeting chromogranin A in humanized NOD mice and type 1 diabetes patients

ChgA has recently been identified as the autoantigen for diabetogenic CD4(+) T cells in NOD mice and T1D patients. However, autoreactive CD8(+) T-cell responses targeting ChgA haven't been studied yet. Here several HLA-A*0201-restricted peptides derived from mChgA and hChgA were selected by an integrated computational prediction approach, followed by an HLA-A*0201 binding assay. MChgA(10-19) and mChgA(43-52) peptides, which bound well with HLA-A*0201 molecule, induced significant proliferation and IFN-gamma-releasing of splenocytes from diabetic NOD.beta 2m(null).HHD mice. Notably, flow cytometry analysis found that mChgA(10-19) and mChgA(43-52) stimulated the production of IFN-gamma, perforin, and IL-17 by splenic CD8(+) T cells of diabetic NOD.beta 2m(null).HHD mice. Furthermore, hChgA(10-19) and hChgA(43-52)-induced IFN-gamma releasing by specific CD8(+) T cells were frequently detected in recent-onset HLA-A*0201-positive T1D patients. Thus, this study demonstrated that autoreactive CD8(+) T cells targeting ChgA were present in NOD.beta 2m(null).HHD mice and T1D patients, and might contribute to pathogenesis of T1D through secreting proinflammatory cytokines and cytotoxic molecules. (C) 2015 The Authors. Published by Elsevier Inc.