Cell Rep 2019 Dec 3; 29(10):3073-3086.e5
DK46266, DK 95735, OD020351
Human genetic studies implicate interleukin-27 (IL-27) in the pathogenesis of type 1 diabetes (T1D), but the underlying mechanisms remain largely unexplored. To further define the role of IL-27 in T1D, we generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27Rα. In contrast to wild-type NOD mice, both NOD.Il27-/- and NOD.Il27ra-/- strains are completely resistant to T1D. IL-27 from myeloid cells and IL-27 signaling in T cells are critical for T1D development. IL-27 directly alters the balance of regulatory T cells (Tregs) and T helper 1 (Th1) cells in pancreatic islets, which in turn modulates the diabetogenic activity of CD8 T cells. IL-27 also directly enhances the effector function of CD8 T cells within pancreatic islets. In addition to T1D, IL-27 signaling in T cells is also required for lacrimal and salivary gland inflammation in NOD mice. Our study reveals that IL-27 contributes to autoimmunity in NOD mice through multiple mechanisms and provides substantial evidence to support its pathogenic role in human T1D.
Ciecko, Ashley E; Foda, Bardees; Barr, Jennifer Y; Ramanathan, Sheela; Atkinson, Mark A; Serreze, David V.; Geurts, Aron M; Lieberman, Scott M; and Chen, Yi-Guang, "Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation." (2019). Faculty Research 2019. 265.