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

doi:10.1016/j.celrep.2019.11.010

Interleukin-27 Is Essential for Type 1 Diabetes Development and Sjögren Syndrome-like Inflammation

Cell Rep. 2019 Dec 3;29(10):3073-3086.e5. doi: 10.1016/j.celrep.2019.11.010.

Authors

Ashley E Ciecko¹, Bardees Foda², Jennifer Y Barr³, Sheela Ramanathan⁴, Mark A Atkinson⁵, David V Serreze⁶, Aron M Geurts⁷, Scott M Lieberman³, Yi-Guang Chen⁸

Affiliations

¹ Department of Microbiology and Immunology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
² 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.
³ Stead Family Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA.
⁴ Department of Immunology and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
⁵ Departments of Pediatrics, and Pathology, Immunology and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, FL 32611, USA.
⁶ The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
⁷ Department of Physiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
⁸ 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. Electronic address: yichen@mcw.edu.

Abstract

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.

Keywords: IL-27; IL-27Ra; NOD mouse; Sjögren syndrome; T cells; T-bet; autoimmunity; insulitis; type 1 diabetes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoimmunity / immunology
CD8-Positive T-Lymphocytes / immunology
Diabetes Mellitus, Type 1 / immunology*
Female
Inflammation / immunology*
Interleukins / immunology*
Islets of Langerhans / immunology
Male
Mice
Mice, Inbred NOD
Sjogren's Syndrome / immunology*
T-Lymphocytes, Regulatory / immunology
Th1 Cells / immunology

Substances

Il27 protein, mouse
Interleukins

Abstract

Publication types

MeSH terms

Substances

Grants and funding