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

Abstract

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. MChgA10-19 and mChgA(43-52) peptides, which bound well with HLA-A*0201 molecule, induced significant proliferation and IFN-γ-releasing of splenocytes from diabetic NOD.β2m(null).HHD mice. Notably, flow cytometry analysis found that mChgA(10-19) and mChgA(43-52) stimulated the production of IFN-γ, perforin, and IL-17 by splenic CD8(+) T cells of diabetic NOD.β2m(null).HHD mice. Furthermore, hChgA(10-19) and hChgA(43-52)-induced IFN-γ 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.β2m(null).HHD mice and T1D patients, and might contribute to pathogenesis of T1D through secreting proinflammatory cytokines and cytotoxic molecules.

Keywords: Chronogranin A; Epitope; Humanized NOD mice; Type 1 diabetes.