Retinoic acid in mucosal immune-regulation

  • Daniel Mucida
  • Hilde Cheroutre
Part of the Progress in Inflammation Research book series (PIR)


The vitamin A metabolite, retinoic acid (RA), and transforming growth factor-ß (TGF-ß) are both abundantly produced in the gut and are known to play significant roles in a variety of developmental processes, including the differentiation of lymphocyte lineages. TGF-ß mediates the direct inhibition of Th1 and Th2 cytokine polarization concomitant with the generation of regulatory T cells (Tregs). Paradoxically, along with inflammatory cytokines such as IL-6, it also induces the differentiation of pro-inflammatory IL-17-producing CD4 helper T cells (Th17). RA, in contrast, is able under certain conditions to stimulate Th2 differentiation and it is a profound inhibitor of IFN-g synthesis. Additionally, RA has been shown to efficiently promote gut tropism. We recently described RA as a key modulator of TGF-ß-driven immune deviation capable of suppressing Th17 differentiation while promoting Foxp3+Treg generation. Here we discuss how RA can affect mucosal immune regulation.


Retinoic Acid Treg Cell Oral Tolerance Retinoic Acid Signaling Oral Tolerance Induction 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Rescigno M, Urbano M, Valzasina B, Francolini M, Rotta G, Bonasio R, Granucci F, Kraehenbuhl JP, Ricciardi-Castagnoli P. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat Immunol 2001; 2:361–7PubMedCrossRefGoogle Scholar
  2. 2.
    Leishman AJ, Naidenko OV, Attinger A, Koning F, Lena CJ, Xiong Y, Chang HC, Reinherz E, Kronenberg M, Cheroutre H. T cell responses modulated through interaction between CD8alphaalpha and the nonclassical MHC class I molecule, TL. Science 2001; 294:1936–9PubMedCrossRefGoogle Scholar
  3. 3.
    Hershberg R, Eghtesady P, Sydora B, Brorson K, Cheroutre H, Modlin R, Kronenberg M. Expression of the thymus leukemia antigen in mouse intestinal epithelium. Proc Natl Acad Sci USA 1990; 87:9727–31PubMedCrossRefGoogle Scholar
  4. 4.
    Cheroutre H. IELs: enforcing law and order in the court of the intestinal epithelium. Immunol Rev 2005; 206:114–31PubMedCrossRefGoogle Scholar
  5. 5.
    Worbs T, Bode U, Yan S, Hoffmann MW, Hintzen G, Bernhardt G, Forster R, Pabst O. Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells. J Exp Med 2006; 203:519–27PubMedCrossRefGoogle Scholar
  6. 6.
    Bilsborough J, George TC, Norment A, Viney JL. Mucosal CD8alpha+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 2003; 108:481–92PubMedCrossRefGoogle Scholar
  7. 7.
    Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity 2004; 21:527–38PubMedCrossRefGoogle Scholar
  8. 8.
    Clagett-Dame M, DeLuca HF. The role of vitamin A in mammalian reproduction and embryonic development. Annu Rev Nutr 2002; 22:347–81PubMedCrossRefGoogle Scholar
  9. 9.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA. Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 2006; 24:99–146PubMedCrossRefGoogle Scholar
  10. 10.
    Mucida D, Kutchukhidze N, Erazo A, Russo M, Lafaille JJ, Curotto de Lafaille MA. Oral tolerance in the absence of naturally occurring Tregs. J Clin Invest 2005; 115:1923–33PubMedCrossRefGoogle Scholar
  11. 11.
    Cantorna MT, Nashold FE, Hayes CE. In vitamin A deficiency multiple mechanisms establish a regulatory T helper cell imbalance with excess Th1 and insufficient Th2 function. J Immunol 1994; 152:1515–22PubMedGoogle Scholar
  12. 12.
    Elias KM, Laurence A, Davidson TS, Stephens G, Kanno Y, Shevach EM, O’Shea JJ. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 2008; 111:1013–20PubMedCrossRefGoogle Scholar
  13. 13.
    Takaki H, Ichiyama K, Koga K, Chinen T, Takaesu G, Sugiyama Y, Kato S, Yoshimura A, Kobayashi T. STAT6 inhibits TGF-beta 1-mediated Foxp3 induction through direct binding to the Foxp3 promoter, which is reverted by retinoic acid receptor. J Biol Chem 2008; 283:14955–62PubMedCrossRefGoogle Scholar
  14. 14.
    Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 2003; 424:88–93PubMedCrossRefGoogle Scholar
  15. 15.
    Papadakis KA, Landers C, Prehn J, Kouroumalis EA, Moreno ST, Gutierrez-Ramos JC, Hodge MR, Targan SR. CC chemokine receptor 9 expression defines a subset of peripheral blood lymphocytes with mucosal T cell phenotype and Th1 or T-regulatory 1 cytokine profile. J Immunol 2003; 171:159–65PubMedGoogle Scholar
  16. 16.
    Svensson M, Marsal J, Ericsson A, Carramolino L, Broden T, Marquez G, Agace WW. CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. J Clin Invest 2002; 110:1113–21PubMedGoogle Scholar
  17. 17.
    Mora JR, Iwata M, Eksteen B, Song SY, Junt T, Senman B, Otipoby KL, Yokota A, Takeuchi H, Ricciardi-Castagnoli P et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 2006; 314:1157–60PubMedCrossRefGoogle Scholar
  18. 18.
    Arthos J, Cicala C, Martinelli E, Macleod K, Van Ryk D, Wei D, Xiao Z, Veenstra TD, Conrad TP, Lempicki RA et al. HIV-1 envelope protein binds to and signals through integrin alpha(4)beta(7), the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9:301–9PubMedCrossRefGoogle Scholar
  19. 19.
    Roberts AB, Sporn MB. Mechanistic interrelationships between two superfamilies: The steroid/retinoid receptors and transforming growth factor-beta. Cancer Surv 1992; 14:205–20PubMedGoogle Scholar
  20. 20.
    Bartholin L, Powers SE, Melhuish TA, Lasse S, Weinstein M, Wotton D. TGIF inhibits retinoid signaling. Mol Cell Biol 2006; 26:990–1001PubMedCrossRefGoogle Scholar
  21. 21.
    Vermot J, Gallego Llamas J, Fraulob V, Niederreither K, Chambon P, Dolle P. Retinoic acid controls the bilateral symmetry of somite formation in the mouse embryo. Science 2005; 308:563–6PubMedCrossRefGoogle Scholar
  22. 22.
    Niederreither K, Subbarayan V, Dolle P, Chambon P. Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 1999; 21:444–8PubMedCrossRefGoogle Scholar
  23. 23.
    Bohnsack BL, Lai L, Dolle P, Hirschi KK. Signaling hierarchy downstream of retinoic acid that independently regulates vascular remodeling and endothelial cell proliferation. Genes Dev 2004; 18:1345–58PubMedCrossRefGoogle Scholar
  24. 24.
    Tabata C, Kubo H, Tabata R, Wada M, Sakuma K, Ichikawa M, Fujita S, Mio T, Mishima M. All-trans retinoic acid modulates radiation-induced proliferation of lung fibroblasts via IL-6/IL-6R system. Am J Physiol Lung Cell Mol Physiol 2006; 290:L597–606PubMedCrossRefGoogle Scholar
  25. 25.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 2007; 317:256–60PubMedCrossRefGoogle Scholar
  26. 26.
    Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med 2007; 204:1765–74PubMedCrossRefGoogle Scholar
  27. 27.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 2007; 204:1775–85PubMedCrossRefGoogle Scholar
  28. 28.
    Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 2007; 204:1757–64PubMedCrossRefGoogle Scholar
  29. 29.
    Yang XO, Panopoulos AD, Nurieva R, Chang SH, Wang D, Watowich SS, Dong C. STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 2007; 282:9358–63PubMedCrossRefGoogle Scholar
  30. 30.
    Denning TL, Granger SW, Mucida D, Graddy R, Leclercq G, Zhang W, Honey K, Rasmussen JP, Cheroutre H, Rudensky AY, Kronenberg M. Mouse TCRalphabeta+CD8alphaalpha intraepithelial lymphocytes express genes that down-regulate their antigen reactivity and suppress immune responses. J Immunol 2007; 178:4230–9PubMedGoogle Scholar
  31. 31.
    Denning TL, Wang YC, Patel SR, Williams IR, Pulendran B. Lamina propria macrophages and dendritic cells differentially induce regulatory and interleukin 17-producing T cell responses. Nat Immunol 2007; 8:1086–94PubMedCrossRefGoogle Scholar
  32. 32.
    Nozaki Y, Yamagata T, Sugiyama M, Ikoma S, Kinoshita K, Funauchi M. Anti-inflammatory effect of all-trans-retinoic acid in inflammatory arthritis. Clin Immunol 2006; 119:272–9PubMedCrossRefGoogle Scholar
  33. 33.
    Hirota K, Hashimoto M, Yoshitomi H, Tanaka S, Nomura T, Yamaguchi T, Iwakura Y, Sakaguchi N, Sakaguchi S. T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis. J Exp Med 2007; 204:41–7PubMedCrossRefGoogle Scholar
  34. 34.
    Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17(+) T helper cells. Cell 2006; 126:1121–33PubMedCrossRefGoogle Scholar
  35. 35.
    Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, Oukka M, Kuchroo VK. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448:484–7PubMedCrossRefGoogle Scholar
  36. 36.
    Nurieva R, Yang XO, Martinez G, Zhang Y, Panopoulos AD, Ma L, Schluns K, Tian Q, Watowich SS, Jetten AM, Dong C. Essential autocrine regulation by IL-21 in the generation of inflammatory T cells. Nature 2007; 448:480–3PubMedCrossRefGoogle Scholar
  37. 37.
    Zhou L, Ivanov II, Spolski R, Min R, Shenderov K, Egawa T, Levy DE, Leonard WJ, Littman DR. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 2007; 8:967–74PubMedCrossRefGoogle Scholar
  38. 38.
    Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z, Yao Z, Blank RB, Meylan F, Siegel R, Hennighausen L et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 2007; 26:371–81PubMedCrossRefGoogle Scholar
  39. 39.
    Winoto A, Littman DR. Nuclear hormone receptors in T lymphocytes. Cell 2002; 109 Suppl: S57–66CrossRefGoogle Scholar
  40. 40.
    Si J, Collins SJ. IL-3-induced enhancement of retinoic acid receptor activity is mediated through Stat5, which physically associates with retinoic acid receptors in an IL-3-dependent manner. Blood 2002; 100:4401–9PubMedCrossRefGoogle Scholar
  41. 41.
    Nakajima H, Brindle PK, Handa M, Ihle JN. Functional interaction of STAT5 and nuclear receptor co-repressor SMRT: implications in negative regulation of STAT5-dependent transcription. EMBO J 2001; 20:6836–44PubMedCrossRefGoogle Scholar
  42. 42.
    Yarmus M, Woolf E, Bernstein Y, Fainaru O, Negreanu V, Levanon D, Groner Y. Groucho/ transducin-like enhancer-of-split (TLE)-dependent and-independent transcriptional regulation by Runx3. Proc Natl Acad Sci USA 2006; 103:7384–9PubMedCrossRefGoogle Scholar
  43. 43.
    Cheroutre H. Starting at the beginning: new perspectives on the biology of mucosal T cells. Annu Rev Immunol 2004; 22:217–46PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2009

Authors and Affiliations

  • Daniel Mucida
    • 1
  • Hilde Cheroutre
    • 1
  1. 1.La Jolla Institute for Allergy and ImmunologyLa JollaUSA

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