In type 1 diabetes (T1D), autoreactive cytotoxic CD8⁺ T cells are implicated in the destruction of insulin-producing β cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8⁺ T cells that recognize peptides presented by these class I molecules on pancreatic β cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8⁺ T cells in HLA-B*3906⁺ children newly diagnosed with T1D and in high-risk HLA-A*2402⁺ children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8⁺ T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906⁺ children with T1D, we observed an increase in PPI_5-12 -specific transitional memory CD8⁺ T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI_5-12 -specific CD8⁺ T cells in HLA-B*3906⁺ children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8⁺ T cells. In longitudinal samples from high-risk HLA-A*2402⁺ children, the percentage of terminal effector cells within the InsB_15-24 -specific CD8⁺ T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8⁺ T cells in T1D. Collectively, our results provide evidence that β cell-reactive CD8⁺ T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.

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