Autoreactive CD8+ T cell exhaustion distinguishes subjects with slow type 1 diabetes progression
Alice E. Wiedeman, … , Peter S. Linsley, S. Alice Long
Alice E. Wiedeman, … , Peter S. Linsley, S. Alice Long
Published December 9, 2019
Citation Information: J Clin Invest. 2020;130(1):480-490. https://doi.org/10.1172/JCI126595.
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Research Article Autoimmunity Immunology

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.

Authors

Alice E. Wiedeman, Virginia S. Muir, Mario G. Rosasco, Hannah A. DeBerg, Scott Presnell, Bertrand Haas, Matthew J. Dufort, Cate Speake, Carla J. Greenbaum, Elisavet Serti, Gerald T. Nepom, Gabriele Blahnik, Anna M. Kus, Eddie A. James, Peter S. Linsley, S. Alice Long

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Figure 4

Age and disease duration do not determine islet-specific CD8+ T cell exhaustion.

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Age and disease duration do not determine islet-specific CD8+ T cell exh...
The frequency of islet-specific phenotypes among islet-specific CD8+ T cells was assessed for subjects with 5 or more Tmr+ events. (A) Frequencies in HCs (n = 13) as a function of age based on DISCOV-R results from Figure 2. Statistical significance was determined by Spearman’s correlation. (B) Frequencies in T1D subjects who were not classified as rapid or slow progressors, grouped by disease duration (<5 years, n = 3, solid orange circles; ≥5 years, n = 5, open purple diamonds) on the basis of DISCOV-R results from Figure 1. A 2-way ANOVA with Sidak’s test for multiple comparisons revealed no statistically significant differences between the groups. Data represent the mean ± SD. (C) Frequencies in T1D subjects (n = 4) with samples drawn at 2 time points following disease onset, shown as paired, stacked bar graphs. The time points of the first draw were 3.2, 3.8, 4.8, and 5.5 years after disease onset, respectively.