Retinoic Acid Imprints Gut-Homing Specificity on T Cells

Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida-shi, Tokyo 194-8511, Japan.
Immunity (Impact Factor: 21.56). 11/2004; 21(4):527-38. DOI: 10.1016/j.immuni.2004.08.011
Source: PubMed


For a preferential homing of T cells to the gut, expression of the integrin alpha4beta7 and the chemokine receptor CCR9 is essential and is induced by antigenic stimulation with dendritic cells from the gut-associated lymphoid organs. Here, we show that the vitamin A (retinol) metabolite, retinoic acid, enhances the expression of alpha4beta7 and CCR9 on T cells upon activation and imprints them with the gut tropism. Dendritic cells from the gut-associated lymphoid organs produced retinoic acid from retinol. The enhanced alpha4beta7 expression on T cells by antigenic stimulation with these dendritic cells was suppressed by the retinal dehydrogenase inhibitor citral and the retinoic acid receptor antagonist LE135. Accordingly, vitamin A deficiency caused a reduction in alpha4beta7(+) memory/activated T cells in lymphoid organs and a depletion of T cells from the intestinal lamina propria. These findings revealed a novel role for retinoic acid in the imprinting of gut-homing specificity on T cells.

11 Reads
    • "The current paradigm of action of retinoid-based therapies is induction of apoptosis and growth arrest (Zhang et al., 2002; Budgin et al., 2005; Nieto- Rementeria et al., 2009). Yet, the natural role of retinoids entails circumventing immune cell trafficking and residence within the skin niche through induction of gut-homing receptors (Iwata et al., 2004; Mora et al., 2008; Guo et al., 2015). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cutaneous T cell lymphoma (CTCL) is a heterogeneous group of malignancies characterized by accumulation of malignant T cells within skin. Retinoids, metabolic derivatives and synthetic analogs of vitamin A, embody an effective CTCL therapy with over three decades of clinical use. The established mechanism of action is induction of growth arrest and apoptosis. However, the natural role of retinoids in T cell biology is imprinting gut-homing properties by inducing integrin α4β7 expression. How the natural role of retinoids relates to therapeutic effectiveness in CTCL has not been addressed and merits investigation. Here we provide evidence that retinoids, including Bexarotene, selectively induce CTCL lineages to increase integrin β7 expression and function prior to growth arrest and apoptosis. Interestingly, augmented CTCL cell adhesion obtained with retinoid exposure was potently attenuated by 1,25-dihydroxyvitamin D3, a metabolic vitamin derivative involved in prompting immune cell skin-homing. The integrin-dependent adhesion changes in CTCL cells occurred through synergistic activation of RAR and RXR nuclear receptors. These data explore the early cellular changes induced by retinoids that may be pivotal to sensitizing CTCL cells to growth arrest and apoptosis.Journal of Investigative Dermatology accepted article preview online, 31 March 2015. doi:10.1038/jid.2015.122.
    Journal of Investigative Dermatology 03/2015; 135(8). DOI:10.1038/jid.2015.122 · 7.22 Impact Factor
  • Source
    • "Retinoic acid has been shown to inhibit Th17 and the conversion of Tregs into T follicular helper cells, and induce intestinal mucosal homing molecules CCR9 and a 4 b 7 (Benson et al. 2007; Iwata et al. 2004; Mora et al. 2003; Mucida et al. 2007; Sun et al. 2007; Takahashi et al. 2012). Also, retinoic acid is important for IgA-secreting cells, since mice deficient for vitamin A lack these cells in the small intestine (Mora et al. 2006). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Our environment poses a constant threat to our health. To survive, all organisms must be able to discriminate between good (food ingredients and microbes that help digest our food) and bad (pathogenic microbes, viruses and toxins). In vertebrates, discrimination between beneficial and harmful antigens mainly occurs at the mucosal surfaces of the respiratory, digestive, urinary and genital tract. Here, an extensive network of cells and organs form the basis of what we have come to know as the mucosal immune system. The mucosal immune system is composed of a single epithelial cell layer protected by a mucus layer. Different immune cells monitor the baso-lateral side of the epithelial cells and dispersed secondary lymphoid organs, such as Peyer's patches and isolated lymphoid follicles are equipped with immune cells able to mount appropriate and specific responses. This review will focus on the current knowledge on host, dietary and bacterial-derived factors that shape the mucosal immune system before and after birth. We will discuss current knowledge on fetal immunity (both responsiveness and lymphoid organ development) as well as the impact of diet and microbial colonization on neonatal immunity and disease susceptibility. Lastly, inflammatory bowel disease will be discussed as an example of how the composition of the microbiota might predispose to disease later in life. A fundamental understanding of the mechanisms involved in mucosal immune development and tolerance will aid nutritional intervention strategies to improve health in neonatal and adult life.
    Archivum Immunologiae et Therapiae Experimentalis 02/2015; 63(4). DOI:10.1007/s00005-015-0329-y · 3.18 Impact Factor
  • Source
    • "In our work we found that RALDH2 can be the responsible for RA synthesis in dLNs. It has been shown that RALDH2 is essential for embryonic development (Duester, 2001), and in immune cells, RALDH2 has been attributed to DCs from mesenteric lymph nodes and also stromal cells (Iwata et al., 2004; Molenaar et al., 2009). These data indicate that in dLNs there are not only RA-sensing cells, such as T cells, but also RA synthesis takes place in the graft dLNs during the allo-response and appears to be essential for T cell function. "
    [Show abstract] [Hide abstract]
    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.
    Immunobiology 01/2015; 220(6). DOI:10.1016/j.imbio.2014.12.018 · 3.04 Impact Factor
Show more


11 Reads
Available from