TY - JOUR AU - Wiedeman, Alice E. AU - Muir, Virginia S. AU - Rosasco, Mario G. AU - DeBerg, Hannah A. AU - Presnell, Scott AU - Haas, Bertrand AU - Dufort, Matthew J. AU - Speake, Cate AU - Greenbaum, Carla J. AU - Serti, Elisavet AU - Nepom, Gerald T. AU - Blahnik, Gabriele AU - Kus, Anna M. AU - James, Eddie A. AU - Linsley, Peter S. AU - Long, S. Alice T1 - Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression PY - 2020/01/02/ AB - Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet β cells at the time of diagnosis, the rate of further β cell loss varies across individuals. It is not clear what drives this differential progression rate. CD8+ T cells have been implicated in the autoimmune destruction of β cells. Here, we addressed whether the phenotype and function of autoreactive CD8+ T cells influence disease progression. We identified islet-specific CD8+ 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+ 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+ 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. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI126595 VL - 130 IS - 1 UR - https://doi.org/10.1172/JCI126595 SP - 480 EP - 490 PB - The American Society for Clinical Investigation ER -