Faculty Collaboration Database

Self-Renewing Islet TCF1⁺ CD8 T Cells Undergo IL-27-Controlled Differentiation to Become TCF1^- Terminal Effectors during the Progression of Type 1 Diabetes. J Immunol 2021 Oct 15;207(8):1990-2004

Date

09/12/2021

Pubmed ID

34507949

Pubmed Central ID

PMC8492517

DOI

10.4049/jimmunol.2100362

Scopus ID

2-s2.0-85116529072 (requires institutional sign-in at Scopus site)   9 Citations

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, CD44^highTCF1⁺CXCR6^- and CD44^highTCF1^-CXCR6⁺, in islets of prediabetic NOD mice. Compared with CD44^highTCF1⁺CXCR6^- CD8 T cells, the CD44^highTCF1^-CXCR6⁺ subset expressed higher levels of inhibitory and cytotoxic molecules and was more prone to apoptosis. Adoptive cell transfer experiments revealed that CD44^highTCF1⁺CXCR6^- CD8 T cells, through continuous generation of the CD44^highTCF1^-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 CD44^highTCF1⁺CXCR6^- population. These results indicate that islet CD44^highTCF1⁺CXCR6^- CD8 T cells are a progenitor-like subset with self-renewing capacity, and, under an IL-27-controlled mechanism, they differentiate into the CD44^highTCF1^-CXCR6⁺ terminal effector population. Our study provides new insight into the sustainability of the CD8 T cell response in the pathogenesis of T1D.

Author List

Ciecko AE, Schauder DM, Foda B, Petrova G, Kasmani MY, Burns R, Lin CW, Drobyski WR, Cui W, Chen YG

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
William R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Chien-Wei Lin PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
CD8-Positive T-Lymphocytes
Cell Differentiation
Cell Self Renewal
Cells, Cultured
Diabetes Mellitus, Type 1
Disease Models, Animal
Disease Progression
Hepatocyte Nuclear Factor 1-alpha
Humans
Insulin-Secreting Cells
Interleukin-27
Mice
Mice, Inbred NOD
T-Lymphocytes, Cytotoxic