CD8+ T cells are perceived to play a major role in the pathogenesis of type 1 diabetes (T1D). In this study, we characterized the function and phenotype of circulating CD8+ memory T cells in samples from individuals at different stages of T1D progression using flow cytometry and single-cell multiomics. We observed two distinct CD8+ T-cell signatures during progression of T1D within the highly differentiated CD27CD8+ memory T cell subset. A proinflammatory signature, with an increased frequency of IFN-γ+TNF-α+ CD27CD8+ memory T cells, was observed in children with newly diagnosed T1D (stage 3) and correlated with the level of dysglycemia at diagnosis. In contrast, a co-inhibitory signature, with an increased frequency of KLRG1+TIGIT+ CD27CD8+ memory T cells, was observed in islet autoantibody-positive children who later progressed to T1D (stage 1). No alterations within CD27CD8+ memory T cells were observed in adults with established T1D or in children during the initial seroconversion to islet autoantibody positivity. Single-cell multiomics analyses suggested that CD27CD8+ T cells expressing the IFNG+TNF+ proinflammatory signature may be distinct from those expressing the KLRG1+TIGIT+ co-inhibitory signature at the single-cell level. Collectively, our findings suggest that distinct blood CD8+ T-cell signatures could be employed as potential biomarkers of T1D progression.

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