Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression

• Published in: The Journal of clinical investigation Vol. 130; no. 1; pp. 480 - 490
• Main Authors: 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., Long, S. Alice
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 02.01.2020
• Subjects: Adolescent; Adult; Antigens; Autoimmunity; Biomedical research; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Child; Child, Preschool; Clinical trials; Cytometry; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - pathology; Disease; Female; Genotype & phenotype; Humans; Immunologic Memory; Immunological memory; Infant; Insulin; Islets of Langerhans - immunology; Islets of Langerhans - pathology; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Male; Memory cells; Middle Aged; Peptides; Phenotypes; Receptor mechanisms; Autoimmunity; Immunology; Diabetes; Autoimmune diseases; T cells
• DOI: 10.1172/JCI126595
• ISSN: 0021-9738; 1558-8238

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.