Type 2 immunity, which involves coordinated regulation of innate and adaptive immune responses, can protect against helminth parasite infection, but may lead to allergy and asthma after inappropriate activation. We demonstrate that il25−/− mice display inefficient Nippostrongylus brasiliensis expulsion and delayed cytokine production by T helper 2 cells. We further establish a key role for interleukin (IL)-25 in regulating a novel population of IL-4–, IL-5–, IL-13–producing non–B/non–T (NBNT), c-kit+, FcɛR1− cells during helminth infection. A deficit in this population in il25−/− mice correlates with inefficient N. brasiliensis expulsion. In contrast, administration of recombinant IL-25 in vivo induces the appearance of NBNT, c-kit+, FcɛR1− cells and leads to rapid worm expulsion that is T and B cell independent, but type 2 cytokine dependent. We demonstrate that these IL-25–regulated cells appear rapidly in the draining lymph nodes, implicating them as a source of type 2 cytokines during initiation of worm expulsion.

No abstract

BackgroundInterleukin-25 (IL-25) is a potent activator of type-2 immune responses. Mucosal inflammation in ulcerative colitis is driven by type-2 cytokines. We have previously shown that a neutralizing anti-IL-25 antibody abrogated airways hyperreactivity in an experimental model of lung allergy. Therefore, we asked whether blocking IL-25 via neutralizing antibodies against the ligand or its receptor IL-17BR could protect against inflammation in an oxazolone-induced mouse model of colitis.MethodsNeutralizing antibodies to IL-25 or IL-17BR were administered to mice with oxazolone-induced colitis, a model of ulcerative colitis. The disease onset was evaluated by weight loss and degree of colon ulceration. Also, lamina propria and mesenteric lymph node (MLN) infiltrates were assessed for mucosal inflammation and cultured in vitro to determine cytokine production.ResultsWe found that in oxazolone colitis IL-25 production derives from intestinal epithelial cells and that IL-17BR+ IL-13-producing natural killer T (NKT) cells and nuocytes drive the intestinal inflammation. Blocking IL-25 signalling considerably improved the clinical aspects of the disease, including weight loss and colon ulceration, and resulted in fewer nuocytes and NKT cells infiltrating the mucosa. The improved pathology correlated with a decrease in IL-13 production by lamina propria cells, a decrease in the production of other type-2 cytokines by MLN cells, and a decrease in blood eosinophilia and IgE.ConclusionIL-25 plays a pro-inflammatory role in the oxazolone colitis model, and neutralizing antibodies to IL-25 or IL-17BR can slow the ongoing inflammation in this disease. Because this model mimics aspects of human ulcerative colitis, these antibodies may represent potential therapeutics for reducing gut inflammation in patients.

Summary Interleukin‐23 (IL‐23) plays an essential role in driving intestinal pathology in experimental models of both T‐cell‐dependent and innate colitis. Furthermore, genome‐wide association studies have identified several single‐nucleotide polymorphisms in the IL‐23 receptor (IL‐23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4+ T helper 17 (Th17) cells, IL‐23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T‐cell activity and inducing the expression of Th17‐type cytokines from non‐T‐cell sources. Here we focus on Th17 cells and their associated cytokines IL‐17A, IL‐17F, IL‐21 and IL‐22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue‐protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL‐17 expression and turn on interferon‐γ production to become Th1‐like ‘ex‐Th17’ cells. Interleukin‐23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL‐23 promotes pathology in the intestinal tract. These ‘ex‐Th17’ cells may contribute to disease pathogenesis through their secretion of pro‐inflammatory mediators.