Heterogeneity of Islet-Infiltrating IL-21+ CD4 T Cells in a Mouse Model of Type 1 Diabetes. J Immunol 2023 Apr 01;210(7):935-946
Date
02/11/2023Pubmed ID
36762954Pubmed Central ID
PMC10483376DOI
10.4049/jimmunol.2200712Scopus ID
2-s2.0-85151043870 (requires institutional sign-in at Scopus site) 4 CitationsAbstract
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, to our knowledge, 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 Ags. 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, that is, less differentiated early effectors, T follicular helper (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.
Author List
Ciecko AE, Wang Y, Harleston S, Drewek A, Serreze DV, Geurts AM, Lin CW, Chen YGAuthors
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin
Yu Wang Research Scientist I in the Data Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCD4-Positive T-Lymphocytes
Diabetes Mellitus, Type 1
Islets of Langerhans
Mice
Mice, Inbred NOD
