Temporal Alterations in CD8⁺ T Cells During the Progression From Stage 1 to Stage 3 Type 1 Diabetes

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 CD27⁻CD8⁺ memory T-cell subset. A proinflammatory signature, with an increased frequency of IFN-γ⁺TNF-α⁺ CD27⁻CD8⁺ 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 coinhibitory signature, with an increased frequency of KLRG1⁺TIGIT⁺ CD27⁻CD8⁺ memory T cells, was observed in islet autoantibody-positive children who later progressed to T1D (stage 1). No alterations within CD27⁻CD8⁺ 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 CD27⁻CD8⁺ T cells expressing the IFNG⁺TNF⁺ proinflammatory signature may be distinct from those expressing the KLRG1⁺TIGIT⁺ coinhibitory 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.

• Blood CD8⁺ T-cell signatures have recently been associated with a slower progression of type 1 diabetes (T1D) after diagnosis and with clinical response to immunotherapy.

• We investigated blood CD8⁺ T-cell signatures in individuals at different stages of T1D progression.

• We observed two distinct CD8⁺ T-cell signatures at different stages of T1D: a proinflammatory signature in children with newly diagnosed T1D (stage 3) and a coinhibitory signature in autoantibody-positive children who later progressed to T1D (stage 1).

• CD8⁺ T-cell signatures could potentially be utilized as biomarkers for evaluating the risk of T1D progression.