Retinoic Acid Imprints Gut-Homing Specificity on T Cells
ABSTRACT 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.
- SourceAvailable from: Sylvia Brugman
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- "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). "
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; DOI:10.1007/s00005-015-0329-y · 2.82 Impact Factor
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- "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. "
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 · 3.18 Impact Factor
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- "Retinoic acid has been shown to mediate mucosal IgA production  and intestinal homing of IgA + plasma cell  and T-cells . In addition to mediating these responses, vitamin A is also essential for normal T-cell responses in the gut mucosa . VAD alters cytokine responses such as polarization toward increased T-helper cell type- 1(Th1) cytokine responses in infants  and mice . "
ABSTRACT: Vitamin A deficiency (VAD) is associated with increased childhood mortality and morbidity in impoverished Asian and African countries, but the impact of VAD on rotavirus (RV) vaccine or infection is poorly understood. We assessed effects of gestational and dietary induced pre- and post-natal VAD and vitamin A supplementation on immune responses to a pentavalent rotavirus vaccine, RotaTeq(®) in a neonatal gnotobiotic pig model. Vaccine efficacy was assessed against virulent G1P (Singh and West, 2004) human rotavirus (HRV) challenge. VAD and vitamin A sufficient (VAS) piglets were derived from dietary VAD and VAS sows, respectively. VAD piglets had significantly lower levels of hepatic vitamin A compared to that of VAS piglets. RotaTeq(®)-vaccinated VAD piglets had 350-fold higher fecal virus shedding titers compared to vaccinated VAS piglets post-challenge. Only 25% of vaccinated non-vitamin A supplemented VAD piglets were protected against diarrhea compared with 100% protection rate in vaccinated non-supplemented VAS piglets post-challenge. Intestinal HRV specific immune responses were compromised in VAD piglets. Vaccinated VAD piglets had significantly lower ileal HRV IgG antibody secreting cell (ASC) responses (pre-challenge) and duodenal HRV IgA ASC responses (post-challenge) compared to vaccinated VAS piglets. Also, intestinal HRV IgA antibody titers were 11-fold lower in vaccinated VAD compared to vaccinated VAS piglets post-challenge. Persistently elevated levels of IL-8, a pro-inflammatory mediator, and lower IL-10 responses (anti-inflammatory) in vaccinated VAD compared to VAS piglets suggest more severe inflammatory responses in VAD piglets post-challenge. Moreover higher IFN-γ responses pre-challenge were observed in VAD compared to VAS piglets. The impaired vaccine-specific intestinal antibody responses and decreased immunoregulatory cytokine responses coincided with reduced protective efficacy of the RV vaccine against virulent HRV challenge in VAD piglets. In conclusion, VAD impaired antibody responses to RotaTeq(®) and vaccine efficacy. Oral supplementation of 100,000IU vitamin A concurrent with RV vaccine failed to increase the vaccine efficacy in VAD piglets.Vaccine 12/2013; 32(7). DOI:10.1016/j.vaccine.2013.12.039 · 3.49 Impact Factor