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

AE Wiedeman, VS Muir, MG Rosasco… - The Journal of …, 2020 - Am Soc Clin Investig
AE Wiedeman, VS Muir, MG Rosasco, HA DeBerg, S Presnell, B Haas, MJ Dufort, C Speake
The Journal of clinical investigation, 2020Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation