Autoreactive T Effector Memory Differentiation Mirrors Beta Cell Function In Type 1 Diabetes

In type 1 diabetes, cytotoxic CD8(+) T cells with specificity for beta cell autoantigens are found in the pancreatic islets, where they are implicated in the destruction of insulin-secreting beta cells. In contrast, the disease relevance of beta cell-reactive CD8(+) T cells that are detectable in the circulation, and their relationship to beta cell function, are not known. Here, we tracked multiple, circulating beta cell-reactive CD8(+) T cell subsets and measured beta cell function longitudinally for 2 years, starting immediately after diagnosis of type 1 diabetes. We found that change in beta 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 beta cell-reactive CD57(+) effector memory CD8(+) T cell subsets were strongly linked. Thus, coordinated changes in circulating beta 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.