Wiedeman, Alice E., Muir, Virginia S., Rosasco, Mario G., DeBerg, Hannah A., Presnell, Scott, Haas, Bertrand, Dufort, Matthew J., Speake, Cate, Greenbaum, Carla J., Serti, Elisavet, Nepom, Gerald T., Blahnik, Gabriele, Kus, Anna M., James, Eddie A., Linsley, Peter S., and Long, S. Alice
Introduction Type 1 diabetes (T1D) is an organ-specific autoimmune disease that leads to the destruction of pancreatic islet [beta] cells, resulting in glucose dysregulation and a life-long dependence on exogenous [...], Although most patients with type 1 diabetes (T1D) 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.sup.+] T cells have been implicated in the autoimmune destruction of [beta] cells. Here, we addressed whether the phenotype and function of autoreactive [CD8.sup.+] T cells influence disease progression. We identified islet-specific [CD8.sup.+] T cells using high-content, single-cell mass cytometry in combination with peptide-loaded MHC tetramer staining. We applied a new analytical method, DISCOV-R, to characterize these rare subsets. Autoreactive T cells were phenotypically heterogeneous, and their phenotype differed by rate of disease progression. Activated islet-specific [CD8.sup.+] memory T cells were prevalent in subjects with T1D who experienced rapid loss of C-peptide; 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. This relationship between properties of autoreactive [CD8.sup.+] T cells and the rate of T1D disease progression after onset make these phenotypes attractive putative biomarkers of disease trajectory and treatment response and reveal potential targets for therapeutic intervention.