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: 21.56). 08/2010; 33(2):279-88. DOI: 10.1016/j.immuni.2010.08.010
Source: PubMed


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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    • "Map has been implicated in the pathogenesis of a variety of inflammatory bowel diseases (Chacon et al., 2004; Davis and Madsen-Bouterse, 2012) and IL-23 has been shown to be a key regulator of inflammation at mucosal surfaces, where dysregulation is linked to these diseases (Ahern et al., 2010; Geremia et al., 2011). IL-12 is not differentially expressed between the pauci-and multibacillary forms in sheep paratuberculosis (Smeed et al., 2007) or between T. circumcincta infected susceptible and resistant sheep (Gossner et al., 2012) implying a possible role for IL-23 in the discrimination of the pathologies. "

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    • "Moreover, Th17 cells are capable of transformation into IFN-γ-producing Th1-like effectors [6][7][8]. This functional change depends on repetitive TCR stimulation and IL-12 or IL-23 signaling [8][9], it increases the pathogenic potential of T cells and is required for development of proper effector responses in vivo [10][11]. One of the mechanisms underlying this phenotypic plasticity might be an unstable pattern of epigenetic modifications within the Tbx21 and Ifng loci in Th17 cells [12]. "
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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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