1. Department of Pathobiology and,
2. Department of Animal Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3. Department of Veterinary Pathology, Free University Berlin, 14163 Berlin, Germany
4. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, and
5. Department of Medicine, University of California San Diego, La Jolla, California 92093, USA
6. Present address: Second Department of Medicine, Technical University Munich, 81675 Munich, Germany.

Correspondence to: David Artis¹ Correspondence and requests for materials should be addressed to D.A. (Email: dartis@vet.upenn.edu).

Abstract

Intestinal epithelial cells (IECs) provide a primary physical barrier against commensal and pathogenic microorganisms in the gastrointestinal (GI) tract, but the influence of IECs on the development and regulation of immunity to infection is unknown¹. Here we show that IEC-intrinsic IB kinase (IKK)--dependent gene expression is a critical regulator of responses of dendritic cells and CD4⁺ T cells in the GI tract. Mice with an IEC-specific deletion of IKK- show a reduced expression of the epithelial-cell-restricted cytokine thymic stromal lymphopoietin in the intestine and, after infection with the gut-dwelling parasite Trichuris, fail to develop a pathogen-specific CD4⁺ T helper type 2 (T_H2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-, increased levels of CD4⁺ T-cell-derived interferon- and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK- in IECs to promote CD4⁺ T_H2 cell-dependent immunity, identifying an essential function for IECs in tissue-specific conditioning of dendritic cells and limiting type 1 cytokine production in the GI tract. These results indicate that the balance of IKK--dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.

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