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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    ABSTRACT: Protein kinase C θ (PKCθ) is involved in signaling downstream of the T cell antigen receptor (TCR) and is important for shaping effector T cell functions and inflammatory disease development. Acquisition of Th1-like effector features by Th17 cells has been linked to increased pathogenic potential. However, the molecular mechanisms underlying Th17/Th1 phenotypic instability remain largely unknown. In the current study, we address the role of PKCθ in differentiation and function of Th17 cells by using genetic knock-out mice. Implementing in vitro (polarizing T cell cultures) and in vivo (experimental autoimmune encephalomyelitis model, EAE) techniques, we demonstrated that PKCθ-deficient CD4+ T cells show normal Th17 marker gene expression (interleukin 17A/F, RORγt), accompanied by enhanced production of the Th1-typical markers such as interferon gamma (IFN-γ) and transcription factor T-bet. Mechanistically, this phenotype was linked to aberrantly elevated Stat4 mRNA levels in PKCθ-/- CD4+ T cells during the priming phase of Th17 differentiation. In contrast, transcription of the Stat4 gene was suppressed in Th17-primed wild-type cells. This change in cellular effector phenotype was reflected in vivo by prolonged neurological impairment of PKCθ-deficient mice during the course of EAE. Taken together, our data provide genetic evidence that PKCθ is critical for stabilizing Th17 cell phenotype by selective suppression of the STAT4/IFN-γ/T-bet axis at the onset of differentiation.
    Full-text · Article · May 2014 · PLoS ONE
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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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    ABSTRACT: NOD2 is an intracellular sensor that contributes to immune defense and inflammation. Here we investigated whether NOD2 mediates its effects through control of microRNAs (miRNAs). miR-29 expression was upregulated in human dendritic cells (DCs) in response to NOD2 signals, and miR-29 regulated the expression of multiple immune mediators. In particular, miR-29 downregulated interleukin-23 (IL-23) by targeting IL-12p40 directly and IL-23p19 indirectly, likely via reduction of ATF2. DSS-induced colitis was worse in miR-29-deficient mice and was associated with elevated IL-23 and T helper 17 signature cytokines in the intestinal mucosa. Crohn's disease (CD) patient DCs expressing NOD2 polymorphisms failed to induce miR-29 upon pattern recognition receptor stimulation and showed enhanced release of IL-12p40 on exposure to adherent invasive E. coli. Therefore, we suggest that loss of miR-29-mediated immunoregulation in CD DCs might contribute to elevated IL-23 in this disease.
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