Self-Renewing Islet TCF1+ CD8 T Cells Undergo IL-27–Controlled Differentiation to Become TCF1− Terminal Effectors during the Progression of Type 1 Diabetes
Year: 2021
Type: article
Abstract: In type 1 diabetes (T1D) autoreactive CD8 T cells infiltrate pancreatic islets and destroy insulin-producing β cells. Progression to T1D onset is a chronic process, which suggests that the effector activity of β-cell autoreactive CD8 T cells needs to be maintained throughout the course of disease development. The mechanism that sustains diabetogenic CD8 T cell effectors during the course of T1D progression has not been completely defined. Here we used single-cell RNA sequencing to gain further insight into the phenotypic complexity of islet-infiltrating CD8 T cells in NOD mice. We identified two functionally distinct subsets of activated CD8 T cells, CD44highTCF1+CXCR6− and CD44highTCF1−CXCR6+, in islets of prediabetic NOD mice. Compared with CD44highTCF1+CXCR6− CD8 T cells, the CD44highTCF1−CXCR6+ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44highTCF1+CXCR6− CD8 T cells, through continuous generation of the CD44highTCF1−CXCR6+ subset, were more capable than the latter population to promote insulitis and the development of T1D. We further showed that direct IL-27 signaling in CD8 T cells promoted the generation of terminal effectors from the CD44highTCF1+CXCR6− population. These results indicate that islet CD44highTCF1+CXCR6− CD8 T cells are a progenitor-like subset with self-renewing capacity, and, under an IL-27–controlled mechanism, they differentiate into the CD44highTCF1−CXCR6+ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.
Source: The Journal of Immunology
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1091786515, G1801027895, G2672754313, G293997312, G3072722385, G322343690, G3223876117, G352720048, G4232855887, G435608594, G4421173750, G5423723476, Cannabinoid-mediated mitigation of graft versus host disease: Roles of CB2 receptors and adenosine signaling, Shaping diabetogenic T cells by IL-27 in type 1 diabetes, G5681813386, G5904669230, G6615645996, G6647092335, Medical Scientist Training Program, G7773696593, Mechanistic and therapeutic role of the CD137-CD137L axis in Type 1 Diabetes, Inflammatory Cytokine Networks in Gastrointestinal Tract Graft Versus Host Disease
OpenAlex ID: W3198720397