Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract involving aberrant activation of innate and adaptive immune responses. We have used two complementary models of IBD to examine the roles of interleukin (IL)-12 family cytokines in bacterially induced intestinal inflammation. Our results clearly show that IL-23, but not IL-12, is essential for the induction of chronic intestinal inflammation mediated by innate or adaptive immune mechanisms. Depletion of IL-23 was associated with decreased proinflammatory responses in the intestine but had little impact on systemic T cell inflammatory responses. These results newly identify IL-23 as a driver of innate immune pathology in the intestine and suggest that selective targeting of IL-23 represents an attractive therapeutic approach in human IBD.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract that is caused in part by a dysregulated immune response to the intestinal flora. The common interleukin (IL)-12/IL-23p40 subunit is thought to be critical for the pathogenesis of IBD. We have analyzed the role of IL-12 versus IL-23 in two models of Helicobacter hepaticus–triggered T cell–dependent colitis, one involving anti–IL-10R monoclonal antibody treatment of infected T cell–sufficient hosts, and the other involving CD4+ T cell transfer into infected Rag−/− recipients. Our data demonstrate that IL-23 and not IL-12 is essential for the development of maximal intestinal disease. Although IL-23 has been implicated in the differentiation of IL-17–producing CD4+ T cells that alone are sufficient to induce autoimmune tissue reactivity, our results instead support a model in which IL-23 drives both interferon γ and IL-17 responses that together synergize to trigger severe intestinal inflammation.

The transcription factor FOXP3 plays a key role in CD4⁺CD25⁺ regulatory T cell function and represents a specific marker for these cells. Despite its strong association with regulatory T cell function, in humans little is known about the frequency of CD4⁺CD25⁺ cells that express FOXP3 protein nor the distribution of these cells in vivo. Here we report the characterization of seven anti‐FOXP3 monoclonal antibodies enabling the detection of endogenous human FOXP3 protein by flow cytometry and immunohistochemistry. Flow‐cytometric analysis showed that FOXP3 was expressed by the majority of CD4⁺CD25^high T cells in peripheral blood. By contrast, less than half of the CD4⁺CD25^int population were FOXP3⁺, providing an explanation for observations in human T cells that regulatory activity is enriched within the CD4⁺CD25^high pool. Although FOXP3 expression was primarily restricted to CD4⁺CD25⁺ cells, it was induced following activation of both CD4⁺ and CD8⁺ T cell clones. These findings indicate that the frequency of FOXP3⁺ cells correlates with the level of expression of CD25 in naturally arising regulatory T cells and that FOXP3 protein is expressed by some activated CD4⁺ and CD8⁺ T cell clones. These reagents represent valuable research tools to further investigate FOXP3 function and are applicable for routine clinical use. See accompanying Commentary http://dx.doi.org/10.1002/eji.200526303

Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.