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

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 I kappa B kinase ( IKK)-beta-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-beta 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-alpha, increased levels of CD4(+) T-cell-derived interferon-gamma and interleukin-17, and develop severe intestinal inflammation. Blockade of proinflammatory cytokines during Trichuris infection ablates the requirement for IKK-beta 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-beta-dependent gene expression in the intestinal epithelium is crucial in intestinal immune homeostasis by promoting mucosal immunity and limiting chronic inflammation.