Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation
Ashley E. Ciecko,
Bardees Foda,
Jennifer Y. Barr,
Sheela Ramanathan,
Mark A. Atkinson,
David V. Serreze,
Aron M. Geurts,
Scott M. Lieberman,
Yi-Guang Chen
Affiliations
Ashley E. Ciecko
Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Bardees Foda
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Molecular Genetics and Enzymology, National Research Centre, Dokki, Egypt
Jennifer Y. Barr
Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA
Sheela Ramanathan
Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
Mark A. Atkinson
Departments of Pediatrics, and Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32611, USA
David V. Serreze
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA
Aron M. Geurts
Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA
Scott M. Lieberman
Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA
Yi-Guang Chen
Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA; Corresponding author
Summary: 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. : Human genetic studies implicate IL-27 in the pathogenesis of type 1 diabetes (T1D). Ciecko et al. demonstrate that IL-27 signaling in T cells changes the balance of regulatory and effector subsets and is critical for T1D development as well as lacrimal and salivary gland inflammation in NOD mice. Keywords: NOD mouse, IL-27, IL-27Ra, type 1 diabetes, T cells, insulitis, T-bet, autoimmunity, Sjögren syndrome
