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IL-27 Regulates Homeostasis of the Intestinal CD4⁺ Effector T Cell Pool and Limits Intestinal Inflammation in a Murine Model of Colitis¹

Amy E. Troy^*, Colby Zaph^2,*, Yurong Du^*, Betsy C. Taylor^*, Katherine J. Guild^*, Christopher A. Hunter^*, Christiaan J. M. Saris and David Artis^3,*

^* Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and Department of Inflammation Research, Amgen, Thousand Oaks, CA 91320

IL-27 limits CD4⁺ T_H17 cell development in vitro and during inflammatory responses in the CNS. However, whether IL-27-IL-27R interactions regulate the homeostasis or function of CD4⁺ T cell populations in the intestine is unknown. To test this, we examined CD4⁺ T cell populations in the intestine of wild-type and IL-27R^–/– mice. Naive IL-27R^–/– mice exhibited a selective decrease in the frequency of IFN- producing CD4⁺ T_H1 cells and an increase in the frequency of T_H17 cells in gut-associated lymphoid tissues. Associated with elevated expression of IL-17A, IL-27R^–/– mice exhibited earlier onset and significantly increased severity of clinical disease compared with wild-type controls in a murine model of intestinal inflammation. Rag^–/–/IL-27R^–/– mice were also more susceptible than Rag^–/– mice to development of dextran sodium sulfate-induced intestinal inflammation, indicating an additional role for IL-27-IL-27R in the regulation of innate immune cell function. Consistent with this, IL-27 inhibited proinflammatory cytokine production by activated neutrophils. Collectively, these data identify a role for IL-27-IL-27R interaction in controlling the homeostasis of the intestinal T cell pool and in limiting intestinal inflammation through regulation of innate and adaptive immune cell function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by National Institutes of Health Grants AI72943 (to A.E.T.), AI61570 (to D.A.), AI074878 (to D.A.), AI42334 (to C.A.H.), and AI41158 (to C.A.H.), the Irvington Institute Fellowship Program of the Cancer Research Institute (to C.Z.), T32-CA09140-30 (to B.T.), the Burroughs Wellcome Fund Investigator in Pathogenesis of Infectious Disease Award (to D.A.), Crohn’s and Colitis Foundation of America William and Shelby Modell Family Foundation Research Award (to D.A.), the Pilot Feasibility Program of the National Institute of Diabetes and Digestive Kidney Diseases (DK50306), the University of Pennsylvania Research Foundation Award (to D.A.), and the University of Pennsylvania Center for Infectious Diseases Pilot Grants (to D.A.).

² Current address: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada V6T 1Z3.

³ Address correspondence and reprint requests to David Artis, Department of Pathobiology, 314 Hill Pavillion, University of Pennsylvania School of Veterinary Medicine, 380 South University Avenue, Philadelphia, PA 19104-4539. E-mail address: dartis{at}vet.upenn.edu

⁴ Abbreviations used in this paper: IBD, inflammatory bowel disease; WT, wild type; mLN, mesenteric lymph node; PEC, peritoneal exudate cell; DSS, dextran sodium sulfate; LTi, lymphoid tissue inducer; LPL, lamina propria lymphocyte; IEL, intraepithelial lymphocyte.