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

Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, England, UK.
Immunity (Impact Factor: 19.75). 08/2010; 33(2):279-88. DOI: 10.1016/j.immuni.2010.08.010
Source: PubMed

ABSTRACT Mutations 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-gamma(+) 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.

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Available from: Chris Schiering, Nov 20, 2014
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    • "A key role for IL-23 in intestinal inflammation has been demonstrated in both innate and T celldependent experimental models of colitis (Yen et al., 2006; Uhlig et al., 2006). IL-23R signaling in T cells leads to enhanced Th17 accumulation, reduced differentiation of FoxP3 + T cells, and reduced T cell IL-10 production (Ahern et al., 2010). In innate colitis, IL-23 directs expression of IL-17 and induction of pathology via innate lymphoid cells (ILCs) (Buonocore et al., 2010). "
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    • "IL-23 is mainly expressed by lamina propria DCs in the terminal ileum of normal mice, which relates to the markedly higher frequency of Th17 cells in the intestinal lamina propria than in peripheral lymphoid tissues [91]. Evidence has shown that IL- 23 may have important immune protective effects in the gut, since CD45RB high CD4 + T cells lacking the IL-23R fail to develop into IFN-γ /IL-17A double producers and do not trigger colitis in the T cell transfer model [125]. On the other hand, IL-22 is well known for its role in promoting intestinal barrier integrity. "
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    • "In contrast, as in other autoimmune disease models, IL-23 accelerates the severity of murine colitis (Ahern et al. 2010). It is generally believed that IL-17-producing cells are protective but that IL-17/IFN-c double producers are pathogenic and IL-23 accelerates the generation of double producers (Ahern et al. 2010; Hirota et al. 2011). IL-17A is also required for Th2-mediated OVAinduced asthmatic reactions in mice (Nakae et al. 2002). "
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