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Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection¹

Jacqueline R. McDermott^*, Neil E. Humphreys^*, Simon P. Forman^*, Debra D. Donaldson and Richard K. Grencis^2,*

^* Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and Department of Respiratory Disease, Wyeth Research, Cambridge, MA 02140

IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4R (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 antagonist. IL-13 expression was induced in non-T intraepithelial CD3^– NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13R1, and after infection, IL-4R. Furthermore, the soluble IL-13 decoy receptor IL-13R2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine.

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