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

- We firstly report that ChgA-specific CD8+ T cells were present in humanized NOD mice and T1D patients.
- ChgA10-19 and ChgA43-52 were identified as novel HLA-A*0201-restricted CD8+ T-cell epitopes.
- mChgA10-19 and mChgA43-52 stimulated the production of IFN-γ, perforin, and IL-17.

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 mChgA43-52 peptides, which bound well with HLA-A*0201 molecule, induced significant proliferation and IFN-γ-releasing of splenocytes from diabetic NOD.β2mnull.HHD mice. Notably, flow cytometry analysis found that mChgA10-19 and mChgA43-52 stimulated the production of IFN-γ, perforin, and IL-17 by splenic CD8+ T cells of diabetic NOD.β2mnull.HHD mice. Furthermore, hChgA10-19 and hChgA43-52-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.β2mnull.HHD mice and T1D patients, and might contribute to pathogenesis of T1D through secreting proinflammatory cytokines and cytotoxic molecules.