| Autor: |
Wiedeman AE; Translational Research Program., Muir VS; Systems Immunology, and., Rosasco MG; Systems Immunology, and., DeBerg HA; Systems Immunology, and., Presnell S; Systems Immunology, and., Haas B; Systems Immunology, and., Dufort MJ; Systems Immunology, and., Speake C; Diabetes Program, Benaroya Research Institute (BRI) at Virginia Mason, Seattle, Washington, USA., Greenbaum CJ; Diabetes Program, Benaroya Research Institute (BRI) at Virginia Mason, Seattle, Washington, USA., Serti E; Immune Tolerance Network (ITN), Bethesda, Maryland, USA., Nepom GT; Translational Research Program.; Immune Tolerance Network (ITN), Bethesda, Maryland, USA., Blahnik G; Translational Research Program., Kus AM; Translational Research Program., James EA; Translational Research Program., Linsley PS; Systems Immunology, and., Long SA; Translational Research Program. |
| Abstrakt: |
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. |
