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Diabetes and other autoimmune endocrine diseases
Oral
Alice Wiedeman, PhD
Benaroya Research Institute
Virginia Muir, Ph.D.
Systems Immunology Division
Benaroya Research Institute at Virginia Mason
Mario Rosasco, PhD
Benaroya Research Institute
Hannah DeBerg, PhD
Benaroya Research Institute
Scott Presnell, PhD
Benaroya Research Institute
Bertrand Haas, PhD
Benaroya Research Institute
Matthew Dufort, PhD
Benaroya Research Institute
Cate Speake, PhD
Diabetes Clinical Research Program
Benaroya Research Institute
Carla Greenbaum, MD
Benaroya Research Institute
Elisavet Serti, PhD
Immune Tolerance Network
Gerald Nepom, PhD
Immune Tolerance Network
Gabriele Blahnik, MS
Benaroya Research Institute
Anna Kus, BS
Benaroya Research Institute
Eddie James, Ph.D.
Translational Research Program
Benaroya Research Institute at Virginia Mason
Peter Linsley, Ph.D.
Systems Immunology Division
Benaroya Research Institute at Virginia Mason
S. Alice Long, PhD
Benaroya Research Institute
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.