Essential Role for Retinoic Acid in the Promotion of CD4(+) T Cell Effector Responses via Retinoic Acid Receptor Alpha

Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Immunity (Impact Factor: 21.56). 03/2011; 34(3):435-47. DOI: 10.1016/j.immuni.2011.03.003
Source: PubMed


Vitamin A and its metabolite, retinoic acid (RA) are implicated in the regulation of immune homeostasis via the peripheral induction of regulatory T cells. Here we showed RA was also required to elicit proinflammatory CD4(+) helper T cell responses to infection and mucosal vaccination. Retinoic acid receptor alpha (RARα) was the critical mediator of these effects. Antagonism of RAR signaling and deficiency in RARα (Rara(-/-)) resulted in a cell-autonomous CD4(+) T cell activation defect, which impaired intermediate signaling events, including calcium mobilization. Altogether, these findings reveal a fundamental role for the RA-RARα axis in the development of both regulatory and inflammatory arms of adaptive immunity and establish nutritional status as a broad regulator of adaptive T cell responses.

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Available from: Guillaume Oldenhove, Apr 01, 2014
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    • "Raldh activity and expression are increased during allograft rejection RA signaling gets triggered during inflammatory processes (Aoyama et al., 2013; Hall et al., 2011a; Pino-Lagos et al., 2011) For example, in transplantation, it has been shown that CD4+ T cells from rejecting dLNs can sense RA in the nucleus, and this signal is crucial for triggering Th1/Th17 cell responses (Pino-Lagos et al., 2011). However, it is not clear if those dLNs have cells capable to synthesize RA. "
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    ABSTRACT: Retinoic acid (RA), a vitamin A metabolite, has been attributed to relevant functions in adaptive immunity. On T cells, the disruption on RA signaling alters both CD4+ and CD8+ T cells effector function. In this study, we evaluated the contribution of RA synthesis during the immune response using an in vivo skin transplantation model. Our data indicates that the frequency and number of cells containing an active retinaldehyde dehydrogenase (RALDH), a key enzyme for RA synthesis, is increased during skin transplant rejection. In addition, we found that the expression of the mRNA coding for the isoform RALDH2 is up-regulated on graft rejecting draining lymph nodes (dLNs) cells. Lastly, we observed that IFN-γ and IL-17 production by ex vivo re-stimulated dLNs cells is greatly increased during rejection, which it turns depends on RA synthesis, as shown in experiments using a specific RALDH inhibitor. Altogether, our data demonstrate that RA synthesis is incremented during the immune response against an allograft, and also indicates that the synthesis of RA is required for cytokine production by dLNs resident T cells. Copyright © 2014 Elsevier GmbH. All rights reserved.
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    • "Its deficiency is associated with squamous metaplasia of the conjunctiva (Mckelvie, 2003). Vitamin A also acts as a mucosal and systemic immune enhancer through immunohomeostasis of CD4þ helper T cells and Treg cells (Hall et al., 2011; Pino-Lagos et al., 2011; Ross, 2012). These cells are part of tumour immuno-surveillance. "
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    • "RA also modulates the differentiation of naïve CD4+ T cells to become Th1, Th2, Th17, or Foxp3+ inducible regulatory T cells [2]–[9]. Because an RA receptor (RAR) α isoform deficiency limits fundamental T cell signaling [10], basal levels of RA may be essential for T-cell activation and the subsequent development of effector T cells. "
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    ABSTRACT: Retinoic acid (RA)-producing dendritic cells (DCs) play critical roles in gut immunity. Retinal dehydrogenase 2 (RALDH2) encoded by Aldh1a2 is a key enzyme for generating RA in DCs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) potently induces RALDH2 expression in DCs in an RA-dependent manner, and RA alone weakly induces the expression. However, how GM-CSF and RA induce RALDH2 expression remains unclear. Here, we show that GM-CSF-induced activation of the transcription factor Sp1 and RA-dependent signaling via the RA receptor (RAR)/retinoid X receptor (RXR) complex contribute to Aldh1a2 expression. The RAR antagonist LE540 and the Sp1 inhibitor mithramycin A inhibited GM-CSF-induced Aldh1a2 expression in fms-related tyrosine kinase 3 ligand-generated bone marrow-derived DCs (BM-DCs). ERK and p38 MAPK inhibitors suppressed GM-CSF-induced nuclear translocation of Sp1 and Aldh1a2 expression. Sp1 and the RARα/RXRα complex bound to GC-rich Sp1-binding sites and an RA response element (RARE) half-site, respectively, near the TATA box in the mouse Aldh1a2 promoter. The DNA sequences around these sites were highly conserved among different species. In the presence of RA, ectopic expression of RARα/RXRα and Sp1 synergistically enhanced Aldh1a2 promoter-reporter activity. GM-CSF did not significantly induce Aldh1a2 expression in plasmacytoid DCs, peritoneal macrophages, or T cells, and the Aldh1a2 promoter in these cells was mostly unmethylated. These results suggest that GM-CSF/RA-induced RALDH2 expression in DCs requires cooperative binding of Sp1 and the RAR/RXR complex to the Aldh1a2 promoter, and can be regulated by a DNA methylation-independent mechanism.
    PLoS ONE 05/2014; 9(5):e96512. DOI:10.1371/journal.pone.0096512 · 3.23 Impact Factor
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