Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T Cells

Philip P Ahern,Chris Schiering,Sofia Buonocore,Fiona Powrie,Mandy J Mcgeachy,Kevin J Maloy,Dan J Cua

doi:10.1016/j.immuni.2011.02.018

Abstract

(Immunity 33, 279–288; August 27, 2010) In this paper, there was an error in Figure 1F . The histology panel on the left is incorrect; it is the same as the image on the right taken in a different frame. Thus, both images depict the liver of a Rag1−/− host transferred with Il23r−/− T cells. The correct image of a representative liver section of a Rag1−/− host transferred with WT T cells is published here, along with the rest of the figure. The authors regret any inconvenience this error has caused. Interleukin-23 Drives Intestinal Inflammation through Direct Activity on T CellsAhern et al.ImmunityAugust 27, 2010In BriefMutations 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. Full-Text PDF Open Access

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

Introduction

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)

Results

Discussion

Conclusion