Identification of the molecular mechanisms of Il-23-driven intestinal inflammation. (360G-Wellcome-086335_Z_08_Z)

Maintenance of the integrity of the gastrointestinal tract requires a delicate balance between proinflammatory T effector cell responses directed at pathogenic organisms and anti-inflammatory T regulatory cell (Treg) responses toward the commensal flora [1]. In individuals suffering from inflammatory bowel diseases (IBD), such as Crohn's disease and ulcerative colitis, this balanced intestinal immunity is perturbed and inappropriate immune reactivity toward components of the intestinal flora results in chronic inflammation of the intestine [2). Unfortunately, current treatment regimens for IBD are associated with considerable side-effects and more specific therapeutic targets are required for the successful treatment of IBD [2). Studies in murine models of IBD have identified the cytokine interleukin 23 (IL-23) as a major driving force of intestinal inflammation. In particular, work in the Powrie lab has shown that IL-23 is essential for the development of T cell dependent colitis [3, 4]. IL-23 drives local tissue-specific inflammation while it has little effect on systemic immune responses [5), suggesting that IL-23 is a potential therapeutic target in IBD. The receptor for IL-23 (IL-23R) is expressed on a variety of innate and adaptive immune cells and mediates its signals mainly through the transcription factor STAT3 [6, 7]. Further support for a role of IL-23 in IBD is provided by genome wide association studies in humans, which have linked polymorphisms in the IL-23R and STAT3 to increased susceptibility to IBD [8, 9]. IL-23 has been shown to have opposing effects on T helper cells producing the pro-inflammatory cytokine IL- 17 (Th17) and Foxp3 Tregs. Naive CD4+ T cells are induced to differentiate into Th17 cells in the presence of TGF-P and pro-inflammatory cytokines IL-6 and/or IL-21. This programme of differentiation is dependent on the activity of the transcription factors RORyt, RORa, IRF-4 and STAT3 [10]. Recent studies have described the emergence of a population ofT cells capable of producing both IL-17 and IFN-y during murine and human IBD [3, 11, 12). Interestingly, in vitro data suggests that IL-23 can induce expression of IFN-y in IL-17-producing T cells [13]. However, the contribution of IFN-y < IL-17 T cells to IBD pathogenesis has not been characterised. In addition to promoting inflammation directly, IL-23 also appears to inhibit Treg cell activity. Activation of naive T cells in the presence of TGF-!3, and in the absence of pro-inflammatory cytokines, leads to the differentiation of Foxp3 Treg cells from naive Foxp3 T cells [14). These induced T regulatory cells share many similarities with thymic-derived natural Tregs and are thought to provide an additional layer of protection from harmful immune responses in the intestine [15]. Recent studies in the Powrie lab have revealed that IL-23 restrains Foxp3 Treg activity to drive T cell dependent colitis [4). Although the mechanisms of this inhibition of Treg activity by IL-23 are unclear, it appears that IL-23 exerts its effects at the level of induction of Foxp3 Tregs from naive T cells. The aim of this project is to identify the molecular mechanisms involved in IL-23-driven intestinal inflammation. The opposing effects of IL-23 on IFN-y IL-17+ and Tregs will be investigated in detail using in vitro assays and established mouse models of IBD.