An interleukin-27-centered cytokine circuit regulates macrophage and T cell interactions in autoimmune diabetes. iScience 2025 Oct 17;28(10):113537
Date
10/06/2025Pubmed ID
41050931Pubmed Central ID
PMC12494592DOI
10.1016/j.isci.2025.113537Scopus ID
2-s2.0-105016644538 (requires institutional sign-in at Scopus site) 1 CitationAbstract
In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, interleukin (IL)-27 stimulates interferon γ (IFNγ) production by CD4 and CD8 T cells and is essential for disease development. Here, we tested the role of IL-27 in cellular communication. Single-cell RNA sequencing and T cell adoptive transfer showed that IL-27 intrinsically controlled the differentiation of islet-infiltrating CD4 T cells by driving them toward an IL-21+ Th1 phenotype. Consequently, IL-27 signaling in CD4 T cells was important for BATF and granzyme B expression in islet CD8 T effectors. BATF overexpression increased the diabetogenic potential of β cell autoreactive CD8 T cells lacking help from CD4 T cell-derived IL-21. Macrophages were the main source of IL-27 in the islets, whose expression correlated with T cell infiltration. IFNγ and CD40 signaling conferred by activated T cells induced macrophage IL-27 production. Collectively, our findings reveal a role for IL-27 in orchestrating interconnected positive feedback loops involving CD4 T cells, CD8 T cells, and macrophages in autoimmune diabetes.
Author List
Ciecko AE, Nabi R, Drewek A, Schauder DM, Zakharov PN, Wan X, Lieberman SM, Cui W, Hessner MJ, Lin CW, Chen YGAuthors
Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of WisconsinMartin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of Wisconsin
