期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 130, 期 1, 页码 480-490出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI126595
关键词
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资金
- ITN
- National Institute of Allergy and Infectious Diseases (NIAID) (NIH grant) [UM1AI109565]
- JDRF [3-SRA-2014-315-M-R]
Although most patients with type 1 diabetes (T1D) retain some functional insulin-producing islet beta cells at the time of diagnosis, the rate of further beta 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 beta 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.
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