Abstract
SummaryMutations in the IL23R gene are linked to inflammatory bowel disease susceptibility. Experimental models have shown that interleukin-23 (IL-23) orchestrates innate and T cell-dependent colitis; however, the cell populations it acts on to induce intestinal immune pathology are unknown. Here, using Il23r−/− T cells, we demonstrated that T cell reactivity to IL-23 was critical for development of intestinal pathology, but not for systemic inflammation. Through direct signaling into T cells, IL-23 drove intestinal T cell proliferation, promoted intestinal Th17 cell accumulation, and enhanced the emergence of an IL-17A+IFN-γ+ population of T cells. Furthermore, IL-23R signaling in intestinal T cells suppressed the differentiation of Foxp3+ cells and T cell IL-10 production. Although Il23r−/− T cells displayed unimpaired Th1 cell differentiation, these cells showed impaired proliferation and failed to accumulate in the intestine. Together, these results highlight the multiple functions of IL-23 signaling in T cells that contribute to its colitogenic activity.
Highlights
The inflammatory bowel diseases (IBDs), comprising Crohn’s Disease (CD) and ulcerative colitis (UC), are severe inflammatory disorders of the gastrointestinal tract whose incidence are on the increase (Xavier and Podolsky, 2007)
IL-23R Expression on T Cells Is Required for Intestinal but Not Systemic Inflammation To assess the role of IL-23R expression on T cells in the development of colitis, we transferred CD4+CD45RBhi cells isolated from wild-type (WT) or Il23rÀ/À mice into B and T cell-deficient Rag1À/À mice, with the latter allowing us to restrict IL-23 responsiveness to the innate immune compartment
As previously described (Powrie et al, 1993; Read et al, 2000), WT CD4+CD45RBhi T cells vigorously expand upon transfer and induce both a systemic inflammatory response and severe colitis (Figures 1A–1F)
Summary
The inflammatory bowel diseases (IBDs), comprising Crohn’s Disease (CD) and ulcerative colitis (UC), are severe inflammatory disorders of the gastrointestinal tract whose incidence are on the increase (Xavier and Podolsky, 2007). Current therapeutic targeting of proinflammatory cytokines such as TNF-a has proved to be effective, but can lead to deleterious side effects and approximately one-third of patients fail to respond (Podolsky, 2002) These results highlight the need for the identification of new and more specific therapeutic targets for the treatment of IBDs. Interleukin-23 (IL-23), a heterodimeric cytokine comprising IL-12p40 and IL-23p19 (Oppmann et al, 2000), is well documented to be critical in the pathogenesis of a number of murine models of autoimmune and inflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), collagen induced arthritis (CIA), and intestinal inflammation (Cua et al, 2003; Hue et al, 2006; Kullberg et al, 2006; Murphy et al, 2003; Uhlig et al, 2006b; Yen et al, 2006). A functional receptor for IL-23 (IL-12Rb1 and IL-23R) (Parham et al, 2002) is expressed on ab and gd T cells as well as innate leukocytes (Awasthi et al, 2009; Parham et al, 2002) and IL-23 signaling is mediated predominantly by the signal transducer and activator of transcription 3 (STAT3) (Parham et al, 2002)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
