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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: 5.36). 05/2010; 184(10):5519-26. DOI: 10.4049/jimmunol.0903942
Source: PubMed

ABSTRACT 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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    • "Given that these effects were observed in mice overexpressing IL-15, the physiological implications of these observations remain to be determined. Nevertheless, since RA is also required for homing and/or differentiation of potentially proinflammatory Th17 cells in the gut mucosa (Cha et al., 2010; Wang et al., 2010), it is possible that RA will have either a tolerogenic or pro-inflammatory role depending on the immunological context. "
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    ABSTRACT: The vitamin A (VA) metabolite all-trans retinoic acid (RA) plays a key role in mucosal immune responses. RA is produced by gut-associated dendritic cells (DC) and is required for generating gut-tropic lymphocytes and IgA-antibody-secreting cells (IgA-ASC). Moreover, RA modulates Foxp3(+) regulatory T cell (T(REG)) and Th17 effector T cell differentiation. Thus, although RA could be used as an effective "mucosal adjuvant" in vaccines, it also appears to be required for establishing intestinal immune tolerance. Here we discuss the roles proposed for RA in shaping intestinal immune responses and tolerance at the gut mucosal interface. We also focus on recent data exploring the mechanisms by which gut-associated DC acquire RA-producing capacity.
    Molecular Aspects of Medicine 11/2011; 33(1):63-76. DOI:10.1016/j.mam.2011.11.001 · 10.30 Impact Factor
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    • "These findings suggest that a synergy between RA and microbial driven signals promote Th17 differentiation in vivo (Figure 2). Importantly, the ability of RA to support Th17 differentiation likely results from combined actions on DCs and T cells, as addition of RA to Th17 polarizing conditions in APC-less cultures did not enhance Th17 differentiation (Wang et al., 2010). "
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    ABSTRACT: Vitamin A elicits a broad array of immune responses through its metabolite, retinoic acid (RA). Recent evidence indicates that loss of RA leads to impaired immunity, whereas excess RA can potentially promote inflammatory disorders. In this review, we discuss recent advances showcasing the crucial contributions of RA to both immunological tolerance and the elicitation of adaptive immune responses. Further, we provide a comprehensive overview of the cell types and factors that control the production of RA and discuss how host perturbations may affect the ability of this metabolite to control tolerance and immunity or to instigate pathology.
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    ABSTRACT: The gastrointestinal tract is replete with commensal microbes and dietary nutrients that provide homeostatic signals. Antigen presenting dendritic cells (DC) residing in the underlying lamina propria (Lp) respond to these signals; however, how they contribute to intestinal T cell homeostasis is unclear. In Chapter 2, LpDC are revealed to uniquely induce naïve T cell differentiation into the Foxp3+ regulatory T cell (Treg) subset. Further, the molecular mechanisms controlling this capacity both in vitro and in vivo are shown to hinge on the vitamin A metabolite, retinoic acid (RA), which LpDC are equipped to synthesize, and the cytokine, TGF-beta. T cell expression of retinoic acid receptor alpha (RARalpha) is shown to be critical for RA to induce enhanced Foxp3+ Treg induction. Chapter 3 extends upon these findings and addresses the influence of the commensal microbiota in the regulation of this pathway. A Toll like receptor (TLR) 9 ligand, commensal derived DNA, is identified as a potent adjuvant in the gut mucosa, which shapes T cell homeostasis in the GI tract. Accordingly Tlr9–⁄– mice display an intestinal site-specific increase in Foxp3+Treg concomitant with a decrease in TH cells. Dysregulation in Foxp3+ Treg/TH homeostasis results in mucosal-specific impaired immune responses in Tlr9–⁄– animals, which can be reversed upon partial depletion of Foxp3+ Treg. Chapter 4 builds upon findings from Chapter 2. The role of vitamin A metabolism in the regulation of mucosal immunity is examined. Vitamin A insufficient (VAI) mice, which lack vitamin A and metabolic derivatives, mount impaired mucosal TH-1 and TH-17 responses. These defects are reversed upon administration of RA. Moreover, Rara–⁄– mice recapitulate the homeostatic and immune defects observed in VAI mice. Strikingly, loss of basal RA/RARalpha signaling hinders early T cell activation events. Cumulatively, the data argue that steady-state cues from microbiota and nutrients shape the inflammatory tone of the Lp to prime mucosal TH responses. These data also identify a fundamental role for vitamin A metabolism in T cell activation and suggest this pathway may have evolved with the development of adaptive CD4+ T cell responses to coordinate host protection.
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