Dendritic cells can prime naïve CD4+ T cells, however we demonstrate that DC-mediated priming is insufficient for the development of TH2 cell-dependent immunity. We identify basophils as a dominant cell population that coexpressed MHC class II and Il4 message following helminth infection. Basophilia was promoted by thymic stromal lymphopoietin (TSLP) and depletion of basophils impaired immunity to helminth infection. In vitro, basophils promoted antigen-specific CD4+ T cell proliferation and IL-4 production and transfer of basophils augmented the expansion of helminth-responsive CD4+ T cells in vivo. Collectively, these studies suggest that MHC class II-dependent interactions between basophils and CD4+ T cells promote TH2 cytokine responses and immunity against helminth infection.

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.

Summary: There is compelling evidence that epithelial cells (ECs) at mucosal surfaces, beyond their role in creating a physical barrier, are integral components of innate and adaptive immunity. The capacity of these cells to license the functions of specific immune cell populations in the airway and gastrointestinal tract offers the prospect of novel therapeutic strategies to target multiple inflammatory diseases in which barrier immunity is dysregulated. In this review, we discuss the critical functions of EC‐derived thymic stromal lymphopoietin (TSLP), interleukin‐25 (IL‐25), and IL‐33 in the development and regulation of T‐helper 2 (Th2) cytokine‐dependent immune responses. We first highlight recent data that have provided new insights into the factors that control expression of this triad of cytokines and their receptors. In addition, we review their proinflammatory and immunoregulatory functions in models of mucosal infection and inflammation. Lastly, we discuss new findings indicating that despite their diverse structural features and differential expression of their receptors, TSLP, IL‐25, and IL‐33 cross‐regulate one another and share overlapping properties that influence Th2 cytokine‐dependent responses at mucosal sites.

Intestinal epithelial cells (IECs) produce thymic stromal lymphopoietin (TSLP); however, the in vivo influence of TSLP–TSLP receptor (TSLPR) interactions on immunity and inflammation in the intestine remains unclear. We show that TSLP–TSLPR interactions are critical for immunity to the intestinal pathogen Trichuris. Monoclonal antibody–mediated neutralization of TSLP or deletion of the TSLPR in normally resistant mice resulted in defective expression of Th2 cytokines and persistent infection. Susceptibility was accompanied by elevated expression of interleukin (IL) 12/23p40, interferon (IFN) γ, and IL-17A, and development of severe intestinal inflammation. Critically, neutralization of IFN-γ in Trichuris-infected TSLPR−/− mice restored Th2 cytokine responses and resulted in worm expulsion, providing the first demonstration of TSLPR-independent pathways for Th2 cytokine production. Additionally, TSLPR−/− mice displayed elevated production of IL-12/23p40 and IFN-γ, and developed heightened intestinal inflammation upon exposure to dextran sodium sulfate, demonstrating a previously unrecognized immunoregulatory role for TSLP in a mouse model of inflammatory bowel disease.

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