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

ABSTRACT: 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.

SUBMITTER: Wiedeman AE

PROVIDER: S-EPMC6934185 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Peripheral autoreactive CD8 T-cell frequencies are too variable to be a reliable predictor of disease progression of human type 1 diabetes.

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| S-EPMC8663791 | biostudies-literature

Cancer-specific type-I interferon receptor signaling promotes cancer stemness and effector CD8+ T-cell exhaustion.

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