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. Here we show that IEC-intrinsic
IkappaB 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.