Diabetes and other autoimmune endocrine diseases
Although most type 1 diabetes (T1D) subjects retain some functional insulin-producing islet beta cells at the time of diagnosis, the rate of further beta cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T cells are implicated in the autoimmune destruction of beta cells. Here, we addressed whether the phenotype and function of autoreactive CD8+ T cells influence disease progression. We identified and characterized islet-specific CD8+ T cells using high-content single-cell mass cytometry in combination with peptide-loaded MHC tetramer staining, and applied a new analytical method, DISCOV-R, for phenotyping these rare subsets. We found that islet-specific CD8+ T cells were phenotypically heterogeneous within an individual, yet several dominant phenotypes were shared across T1D subjects. One shared phenotype resembled activated memory cells and was significantly more frequent among rapid progressors. In contrast, slow disease progression was associated with an exhaustion-like profile, with expression of multiple inhibitory receptors, limited cytokine production, and reduced proliferative capacity. Increased exhaustion was not solely driven by disease duration, indicating that additional mechanisms influence exhaustion of autoreactive T cells. Thus, we linked the exhaustion of islet-specific CD8+ T cells with the rate of T1D disease progression, suggesting potential benefit of therapeutics which augment T cell exhaustion.