Epithelial-cell-intrinsic IKK-β expression regulates intestinal immune homeostasis

• Published in: Nature (London) 2007-03, Vol.446 (7135), p.552-556
• Main Authors: Zaph, Colby, Troy, Amy E., Taylor, Betsy C., Berman-Booty, Lisa D., Guild, Katherine J., Du, Yurong, Yost, Evan A., Gruber, Achim D., May, Michael J., Greten, Florian R., Eckmann, Lars, Karin, Michael, Artis, David
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; Cytokines - deficiency; Cytokines - immunology; Dendritic Cells - immunology; Epithelial Cells - enzymology; Epithelial Cells - metabolism; Gene Expression Regulation, Enzymologic; Homeostasis; Humanities and Social Sciences; I-kappa B Kinase - genetics; I-kappa B Kinase - metabolism; Immunity, Mucosal - immunology; Infectious diseases; Interferon-gamma - immunology; Interleukin-17 - immunology; Intestines - cytology; Intestines - immunology; Intestines - parasitology; letter; Medical sciences; Mice; multidisciplinary; NF-kappa B - metabolism; Science; Science (multidisciplinary); Trichuris - immunology; Trichuris - physiology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature05590

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 unknown 1 . Here we show that IEC-intrinsic IκB kinase (IKK)-β-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-β 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 H 2) response and are unable to eradicate infection. Further, these animals show exacerbated production of dendritic-cell-derived interleukin-12/23p40 and tumour necrosis factor-α, increased levels of CD4 + T-cell-derived interferon-γ and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-β in IECs to promote CD4 + T H 2 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-β-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.