Autoreactive T effector memory differentiation mirrors β cell function in type 1 diabetes

In type 1 diabetes, cytotoxic CD8⁺ T cells with specificity for β cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting β cells. In contrast, the disease relevance of β cell-reactive CD8⁺ T cells that are detectable in the circulation, and their relationship to β cell function, are not known. Here, we tracked multiple, circulating β cell-reactive CD8⁺ T cell subsets and measured β cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in β cell-specific effector memory CD8⁺ T cells expressing CD57 was positively correlated with C-peptide change in subjects below 12 years of age. Autoreactive CD57+ effector memory CD8⁺ T cells bore the signature of enhanced effector function (higher expression of granzyme B, killer-specific protein of 37 kDa, and CD16, and reduced expression of CD28) compared with their CD57-counterparts, and network association modeling indicated that the dynamics of β cell-reactive CD57+ effector memory CD8⁺ T cell subsets were strongly linked. Thus, coordinated changes in circulating β cell-specific CD8⁺ T cells within the CD57+ effector memory subset calibrate to functional insulin reserve in type 1 diabetes, providing a tool for immune monitoring and a mechanism-based target for immunotherapy.