Heterogeneity of islet-infiltrating interleukin-21+ CD4 T cells in a mouse model of type 1 diabetes

• Published in: The Journal of immunology (1950) 2023-04, Vol.210 (7), p.935-946
• Main Authors: Ciecko, Ashley E., Wang, Yu, Harleston, Stephanie, Drewek, Amber, Serreze, David V., Geurts, Aron M., Lin, Chien-Wei, Chen, Yi-Guang
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2200712

Interleukin (IL)-21 is essential for type 1 diabetes (T1D) development in the NOD mouse model. IL-21-expressing CD4 T cells are present in pancreatic islets where they contribute to T1D progression. However, little is known about their phenotype and differentiation states. To fill this gap, we generated a novel IL-21 reporter NOD strain to further characterize IL-21 + CD4 T cells in T1D. IL-21 + CD4 T cells accumulate in pancreatic islets and recognize β-cell antigens. Single-cell RNA sequencing revealed that CD4 T effector cells in islets actively express IL-21 and they are highly diabetogenic despite expressing multiple inhibitory molecules, including PD-1 and LAG3. Islet IL-21 + CD4 T cells segregate into four phenotypically and transcriptionally distinct differentiation states, less differentiated early effectors, Tfh-like cells, and two Th1 subsets. Trajectory analysis predicts that early effectors differentiate into both Tfh-like and terminal Th1 cells. We further demonstrated that intrinsic IL-27 signaling controls the differentiation of islet IL-21 + CD4 T cells, contributing to their helper function. Collectively, our study reveals the heterogeneity of islet-infiltrating IL-21 + CD4 T cells and indicates that both Tfh-like and Th1 subsets produce IL-21 throughout their differentiation process, highlighting the important sources of IL-21 in T1D pathogenesis.