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J Clin Invest. 2020 Jan 2;130(1):480-490. doi: 10.1172/JCI126595.

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

Author information

1
Translational Research Program.
2
Systems Immunology, and.
3
Diabetes Program, Benaroya Research Institute (BRI) at Virginia Mason, Seattle, Washington, USA.
4
Immune Tolerance Network (ITN), Bethesda, Maryland, USA.

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.

KEYWORDS:

Autoimmune diseases; Autoimmunity; Diabetes; Immunology; T cells

PMID:
31815738
PMCID:
PMC6934185
[Available on 2020-04-02]
DOI:
10.1172/JCI126595
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