Retinoic Acid Determines the Precise Tissue Tropism of Inflammatory Th17 Cells in the Intestine

Laboratory of Immunology and Hematopoiesis, Department of Comparative Pathobiology, Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, USA.
The Journal of Immunology (Impact Factor: 4.92). 05/2010; 184(10):5519-26. DOI: 10.4049/jimmunol.0903942
Source: PubMed


Th17 cells are major effector T cells in the intestine, but the regulation of their tissue tropism within the gut is poorly understood. We investigated the roles of vitamin A and retinoic acid in generation of inflammatory Th17 cells with distinct tissue tropisms within the intestine. We found that Th17 cells with distinct tissue tropisms and pathogenic activities are generated depending on the available concentration of retinoic acid (RA). In contrast to the widespread perception that RA would suppress the generation of Th17 cells, we provide evidence that RA is actually required for generation of Th17 cells with specific tissue tropisms within the gut. Th17 cells induced at suboptimal serum concentrations of RA migrated and induced moderate inflammation mainly in the large intestine, whereas the Th17 cells induced with optimal levels of exogenous RA (approximately 10 nM) migrated to the small intestine and induced more severe inflammation. The Th17 cells, induced in the presence or absence of RA, differentially expressed the trafficking receptors CCR9 and alpha4beta7. CCR9 is required for Th17 cell migration to the small intestine, whereas alpha4beta7 is required for the migration of Th17 cells throughout the whole intestine. Our results identified RA as a major signal that regulates the generation of gut Th17 cells with distinct capacities in migration and inflammatory activities. The results indicate also that specific gut tropism of Th17 cells is determined by the combination of trafficking receptors regulated by the RA signal.

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Available from: Chuanwu Wang, Oct 13, 2015
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    • "Since the Th1 response is the most efficient host response against Eimeria infection, it is conceivable that neutralization of IL17A increases the efficacy of the Th1 response against E. tenella. Although Th17 cells have been reported to be the major effector T cells that provide immunity in the intestine [39] against many potential pathogens [40,41], the exact roles of Th17 cells in the intestine are incompletely understood. Studies by Zhang et al. [26] and Stange et al. [29], in addition to our current report, support the notion that IL17A has a role in E. tenella pathogenesis. "
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    ABSTRACT: Although IL17A is associated with the immunological control of various infectious diseases, its role in host response to Eimeria infections is not well understood. In an effort to better dissect the role of IL17A in host-pathogen interactions in avian coccidiosis, a neutralizing antibody (Ab) to chicken IL17A was used to counteract IL17A bioactivity in vivo. Chickens infected with Eimeria tenella and treated intravenously with IL17A Ab, exhibited reduced intracellular schizont and merozoite development, diminished lesion score, compared with untreated controls. Immunohistological evaluation of cecal lesions in the parasitized tissues indicated reduced migration and maturation of second-generation schizonts and reduced lesions in lamina propria and submucosa. In contrast, untreated and infected chickens had epithelial cells harboring second-generation schizonts, which extend into the submucosa through muscularis mucosa disruptions, maturing into second generation merozoites. Furthermore, IL17A Ab treatment was associated with increased parameters of Th1 immunity (IL2- and IFNgamma- producing cells), reduced levels of reactive oxygen species (ROS), and diminished levels of serum matrix metalloproteinase-9 (MMP-9). Finally, schizonts from untreated and infected chickens expressed S100, Wiskott-Aldrich syndrome protein family member 3 (WASF3), and heat shock protein-70 (HSP70) proteins as merozoites matured, whereas the expression of these proteins was absent in IL17A Ab-treated chickens. These results provide the first evidence that the administration of an IL17A neutralizing Ab to E. tenella-infected chickens inhibits the migration of parasitized epithelial cells, markedly reduces the production of ROS and MMP-9, and decreases cecal lesions, suggesting that IL17A might be a potential therapeutic target for coccidiosis control.
    Veterinary Research 02/2014; 45(1):25. DOI:10.1186/1297-9716-45-25 · 2.82 Impact Factor
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    • "Synthesis of RA from vitamin A is a tightly controlled process that enables specialized cells such as dendritic cells (DCs) to modulate the activation, gut homing ability and function of CD4+ T cells [5]. Additionally, RA has been shown to strongly promote the differentiation of inducible regulatory T cells (iTreg cells) in the presence of TGF-β [6] and can modulate the migration and function of T helper 17 (TH17) cells in the intestine [7]. Interestingly, it has recently been shown that RA signaling occurs in T cells during the early stages of inflammation [8], suggesting that RA may be required for optimal effector T cell responses. "
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    ABSTRACT: The vitamin A metabolite retinoic acid (RA) has potent immunomodulatory properties that affect T cell differentiation, migration and function. However, the precise role of RA metabolism in T cells remains unclear. Catabolism of RA is mediated by the Cyp26 family of cytochrome P450 oxidases. We examined the role of Cyp26b1, the T cell-specific family member, in CD4(+) T cells. Mice with a conditional knockout of Cyp26b1 in T cells (Cyp26b1 (-/-) mice) displayed normal lymphoid development but showed an increased sensitivity to serum retinoids, which led to increased differentiation under both inducible regulatory T (iTreg) cell- and TH17 cell-polarizing conditions in vitro. Further, Cyp26b1 expression was differentially regulated in iTreg and TH17 cells. Transfer of naïve Cyp26b1 (-/-) CD4(+) T cells into Rag1 (-/-) mice resulted in significantly reduced disease in a model of T cell-dependent colitis. Our results show that T cell-specific expression of Cyp26b1 is required for the development of T cell-mediated colitis and may be applicable to the development of therapeutics that target Cyp26b1 for the treatment of inflammatory bowel disease.
    PLoS ONE 08/2013; 8(8):e72308. DOI:10.1371/journal.pone.0072308 · 3.23 Impact Factor
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    • "CD has historically been associated with a Th1-type T-cell mediated inflammation, but in more recent years the role of IL-17 secreting Th17 cells have been discovered [24]. AtRA has been shown to be important both for induction and homing of Th17 cells [25] and mice fed with vitamin A-free diet had lower frequency of Th17 cells [26]. Interestingly, the observed associations with the CYP26B1 rs2241057 polymorphism were significant for CD patients with inflammatory behavior or young age at diagnosis, and not for patients with the other sub-phenotypes of CD. "
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    ABSTRACT: Several studies suggest that Vitamin A may be involved in the pathogenesis of inflammatory bowel disease (IBD), but the mechanism is still unknown. Cytochrome P450 26 B1 (CYP26B1) is involved in the degradation of retinoic acid and the polymorphism rs2241057 has an elevated catabolic function of retinoic acid, why we hypothesized that the rs2241057 polymorphism may affect the risk of Crohn's disease (CD) and Ulcerative Colitis (UC). DNA from 1378 IBD patients, divided into 871 patients with CD and 507 with UC, and 1205 healthy controls collected at Örebro University Hospital and Karolinska University Hospital were analyzed for the CYP26B1 rs2241057 polymorphism with TaqMan® SNP Genotyping Assay followed by allelic discrimination analysis. A higher frequency of patients homozygous for the major (T) allele was associated with CD but not UC compared to the frequency found in healthy controls. A significant association between the major allele and non-stricturing, non-penetrating phenotype was evident for CD. However, the observed associations reached borderline significance only, after correcting for multiple testing. We suggest that homozygous carriers of the major (T) allele, relative to homozygous carriers of the minor (C) allele, of the CYP26B1 polymorphism rs2241057 may have an increased risk for the development of CD, which possibly may be due to elevated levels of retinoic acid. Our data may support the role of Vitamin A in the pathophysiology of CD, but the exact mechanisms remain to be elucidated.
    PLoS ONE 08/2013; 8(8):e72739. DOI:10.1371/journal.pone.0072739 · 3.23 Impact Factor
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