Organisms need to protect themselves against potential dangers from their surroundings, yet they require constant and intimate interactions with the same environment for their survival. The immune system is instrumental for protection against invading organisms and their toxins. The immune system consists of many cell types and is highly integrated within other tissues. Immune activity is particularly enriched at surfaces that separate the host from its environment, such as the skin and the gastrointestinal tract. This enables protection at sites directly at risk but also enables environmental factors to influence the maturation and function of immune structures and cells. Recent work has indicated that the diet in particular is able to influence the immune system and thus affect the development of inflammatory disease. This review aims to highlight recent work on how external factors, with a focus on those derived from the diet such as vitamin A, can have a direct or indirect deterministic influence on the activity and function of immunity.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hooper, L.V. & Macpherson, A.J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).
Randall, T.D., Carragher, D.M. & Rangel-Moreno, J. Development of secondary lymphoid organs. Annu. Rev. Immunol. 26, 627–650 (2008).
Amarasekera, M., Prescott, S.L. & Palmer, D.J. Nutrition in early life, immune-programming and allergies: the role of epigenetics. Asian Pac. J. Allergy Immunol. 31, 175–182 (2013).
Palmer, A.C. Nutritionally mediated programming of the developing immune system. Adv Nutr 2, 377–395 (2011).
Rytter, M.J., Kolte, L., Briend, A., Friis, H. & Christensen, V.B. The immune system in children with malnutrition–a systematic review. PLoS ONE 9, e105017 (2014).
Kadow, S. et al. Aryl hydrocarbon receptor is critical for homeostasis of invariant γδ T cells in the murine epidermis. J. Immunol. 187, 3104–3110 (2011).
Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011).
Hayday, A.C. γδ T cells and the lymphoid stress-surveillance response. Immunity 31, 184–196 (2009).
Komano, H. et al. Homeostatic regulation of intestinal epithelia by intraepithelial γδ T cells. Proc. Natl. Acad. Sci. USA 92, 6147–6151 (1995).
Shires, J., Theodoridis, E. & Hayday, A.C. Biological insights into TCRγδ+ and TCRαβ+ intraepithelial lymphocytes provided by serial analysis of gene expression (SAGE). Immunity 15, 419–434 (2001).
Stange, J. & Veldhoen, M. The aryl hydrocarbon receptor in innate T cell immunity. Semin. Immunopathol. 35, 645–655 (2013).
Turchinovich, G. & Hayday, A.C. Skint-1 identifies a common molecular mechanism for the development of interferon-γ -secreting versus interleukin-17-secreting γδ T cells. Immunity 35, 59–68 (2011).
Hayday, A.C. γδ cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18, 975–1026 (2000).
Zaid, A. et al. Persistence of skin-resident memory T cells within an epidermal niche. Proc. Natl. Acad. Sci. USA 111, 5307–5312 (2014).
Conti, H.R. et al. Oral-resident natural Th17 cells and γδ T cells control opportunistic Candida albicans infections. J. Exp. Med. 211, 2075–2084 (2014).
Conti, H.R. et al. Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J. Exp. Med. 206, 299–311 (2009).
Puel, A. et al. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity. Science 332, 65–68 (2011).
Kotake, S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).
Kurasawa, K. et al. Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 43, 2455–2463 (2000).
Lock, C. et al. Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat. Med. 8, 500–508 (2002).
Ziolkowska, M. et al. High levels of IL-17 in rheumatoid arthritis patients: IL-15 triggers in vitro IL-17 production via cyclosporin A-sensitive mechanism. J. Immunol. 164, 2832–2838 (2000).
Nakae, S. et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17, 375–387 (2002).
Kleinewietfeld, M. et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518–522 (2013).
Wu, C. et al. Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513–517 (2013).
Ivanov, I.I. et al. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine. Cell Host Microbe 4, 337–349 (2008).
Ivanov, I.I. & Honda, K. Intestinal commensal microbes as immune modulators. Cell Host Microbe 12, 496–508 (2012).
Goodnow, C.C., Vinuesa, C.G., Randall, K.L., Mackay, F. & Brink, R. Control systems and decision making for antibody production. Nat. Immunol. 11, 681–688 (2010).
Karrer, U. et al. On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11−/−) mutant mice. J. Exp. Med. 185, 2157–2170 (1997).
Eberl, G. From induced to programmed lymphoid tissues: the long road to preempt pathogens. Trends Immunol. 28, 423–428 (2007).
Eberl, G. & Sawa, S. Opening the crypt: current facts and hypotheses on the function of cryptopatches. Trends Immunol. 31, 50–55 (2010).
Kanamori, Y. et al. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184, 1449–1459 (1996).
van de Pavert, S.A. & Mebius, R.E. New insights into the development of lymphoid tissues. Nat. Rev. Immunol. 10, 664–674 (2010).
Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).
Kiss, E.A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).
Pabst, O. et al. Adaptation of solitary intestinal lymphoid tissue in response to microbiota and chemokine receptor CCR7 signaling. J. Immunol. 177, 6824–6832 (2006).
Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2012).
McDade, T.W., Beck, M.A., Kuzawa, C. & Adair, L.S. Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence. Am. J. Clin. Nutr. 74, 543–548 (2001).
Moore, S.E. et al. Birth weight predicts response to vaccination in adults born in an urban slum in Lahore, Pakistan. Am. J. Clin. Nutr. 80, 453–459 (2004).
Moore, S.E. et al. Revaccination does not improve an observed deficit in antibody responses in Pakistani adults born of a lower birth weight. Vaccine 26, 158–165 (2008).
Victora, C.G. et al. Influence of birth weight on mortality from infectious diseases: a case-control study. Pediatrics 81, 807–811 (1988).
Ahmed, F., Jones, D.B. & Jackson, A.A. Effect of undernutrition on the immune response to rotavirus infection in mice. Ann. Nutr. Metab. 34, 21–31 (1990).
Chandra, R.K. Antibody formation in first and second generation offspring of nutritionally deprived rats. Science 190, 289–290 (1975).
Chandra, R.K. & Wadhwa, M. Nutritional modulation of intestinal mucosal immunity. Immunol. Invest. 18, 119–126 (1989).
Klein, L., Kyewski, B., Allen, P.M. & Hogquist, K.A. Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat. Rev. Immunol. 14, 377–391 (2014).
PrabhuDas, M. et al. Challenges in infant immunity: implications for responses to infection and vaccines. Nat. Immunol. 12, 189–194 (2011).
van de Pavert, S.A. et al. Maternal retinoids control type 3 innate lymphoid cells and set the offspring immunity. Nature 508, 123–127 (2014).
Liu, X. et al. Vitamin A supplementation in early life enhances the intestinal immune response of rats with gestational vitamin A deficiency by increasing the number of immune cells. PLoS ONE 9, e114934 (2014).
Veldhoen, M. & Veiga-Fernandes, H. Feeding immunity: skepticism, delicacies and delights. Nat. Immunol. 16, 215–219 (2015).
Ashworth, A. Effects of intrauterine growth retardation on mortality and morbidity in infants and young children. Eur. J. Clin. Nutr. 52, S34–S41 (1998).
Vlasova, A.N., Chattha, K.S., Kandasamy, S., Siegismund, C.S. & Saif, L.J. Prenatally acquired vitamin A deficiency alters innate immune responses to human rotavirus in a gnotobiotic pig model. J. Immunol. 190, 4742–4753 (2013).
Sirisinha, S., Suskind, R., Edelman, R., Asvapaka, C. & Olson, R.E. Secretory and serum IgA in children with protein-calorie malnutrition. Pediatrics 55, 166–170 (1975).
Moore, S.E. et al. Prenatal or early postnatal events predict infectious deaths in young adulthood in rural Africa. Int. J. Epidemiol. 28, 1088–1095 (1999).
Moore, S.E. et al. Season of birth predicts mortality in rural Gambia. Nature 388, 434 (1997).
Moore, S.E., Collinson, A.C., Tamba N'Gom, P., Aspinall, R. & Prentice, A.M. Early immunological development and mortality from infectious disease in later life. Proc. Nutr. Soc. 65, 311–318 (2006).
Fawzi, W.W., Chalmers, T.C., Herrera, M.G. & Mosteller, F. Vitamin A supplementation and child mortality. A meta-analysis. J. Am. Med. Assoc. 269, 898–903 (1993).
Glasziou, P.P. & Mackerras, D.E. Vitamin A supplementation in infectious diseases: a meta-analysis. Br. Med. J. 306, 366–370 (1993).
WHO. Global prevalence of vitamin A deficiency in populations at risk 1995–2005. WHO Global Database on Vitamin A Deficiency (World Health Organization, Geneva, 2009).
WHO. Randomised trial to assess benefits and safety of vitamin A supplementation linked to immunisation in early infancy. Lancet 352, 1257–1263 (1998).
Darboe, M.K. et al. Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial. Lancet 369, 2088–2096 (2007).
McIntosh, B.E., Hogenesch, J.B. & Bradfield, C.A. Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu. Rev. Physiol. 72, 625–645 (2010).
Fernandez-Salguero, P. et al. Immune system impairment and hepatic fibrosis in mice lacking the dioxin-binding Ah receptor. Science 268, 722–726 (1995).
Bjeldanes, L.F., Kim, J.Y., Grose, K.R., Bartholomew, J.C. & Bradfield, C.A. Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc. Natl. Acad. Sci. USA 88, 9543–9547 (1991).
Rannug, A. et al. Certain photooxidized derivatives of tryptophan bind with very high affinity to the Ah receptor and are likely to be endogenous signal substances. J. Biol. Chem. 262, 15422–15427 (1987).
Moura-Alves, P. et al. AhR sensing of bacterial pigments regulates antibacterial defence. Nature 512, 387–392 (2014).
Ciolino, H.P., Daschner, P.J. & Yeh, G.C. Dietary flavonols quercetin and kaempferol are ligands of the aryl hydrocarbon receptor that affect CYP1A1 transcription differentially. Biochem. J. 340, 715–722 (1999).
Ross, J.A. & Kasum, C.M. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu. Rev. Nutr. 22, 19–34 (2002).
Ciolino, H.P., Daschner, P.J., Wang, T.T. & Yeh, G.C. Effect of curcumin on the aryl hydrocarbon receptor and cytochrome P450 1A1 in MCF-7 human breast carcinoma cells. Biochem. Pharmacol. 56, 197–206 (1998).
Mohammadi-Bardbori, A., Bengtsson, J., Rannug, U., Rannug, A. & Wincent, E. Quercetin, resveratrol, and curcumin are indirect activators of the aryl hydrocarbon receptor (AHR). Chem. Res. Toxicol. 25, 1878–1884 (2012).
Gu, Y.Z., Hogenesch, J.B. & Bradfield, C.A. The PAS superfamily: sensors of environmental and developmental signals. Annu. Rev. Pharmacol. Toxicol. 40, 519–561 (2000).
Schmidt, J.V., Su, G.H., Reddy, J.K., Simon, M.C. & Bradfield, C.A. Characterization of a murine Ahr null allele: involvement of the Ah receptor in hepatic growth and development. Proc. Natl. Acad. Sci. USA 93, 6731–6736 (1996).
Shimizu, Y. et al. Benzo[a]pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 97, 779–782 (2000).
Lee, J.S. et al. AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat. Immunol. 13, 144–151 (2012).
Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).
Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).
Quintana, F.J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008).
Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).
Wolk, K., Witte, E., Witte, K., Warszawska, K. & Sabat, R. Biology of interleukin-22. Semin. Immunopathol. 32, 17–31 (2010).
Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).
Martin, B., Hirota, K., Cua, D.J., Stockinger, B. & Veldhoen, M. Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals. Immunity 31, 321–330 (2009).
Nakajima, K. et al. The ARNT-STAT3 axis regulates the differentiation of intestinal intraepithelial TCRαβ+CD8αα+ cells. Nat. Commun. 4, 2112 (2013).
Chmill, S., Kadow, S., Winter, M., Weighardt, H. & Esser, C. 2,3,7,8-Tetrachlorodibenzo-p-dioxin impairs stable establishment of oral tolerance in mice. Toxicol. Sci. 118, 98–107 (2010).
Esser, C., Rannug, A. & Stockinger, B. The aryl hydrocarbon receptor in immunity. Trends Immunol. 30, 447–454 (2009).
Fritsche, E. et al. Lightening up the UV response by identification of the arylhydrocarbon receptor as a cytoplasmatic target for ultraviolet B radiation. Proc. Natl. Acad. Sci. USA 104, 8851–8856 (2007).
Rannug, U. et al. Structure elucidation of two tryptophan-derived, high affinity Ah receptor ligands. Chem. Biol. 2, 841–845 (1995).
Chennupati, V. et al. Intra- and intercompartmental movement of γδ T cells: intestinal intraepithelial and peripheral γδ T cells represent exclusive nonoverlapping populations with distinct migration characteristics. J. Immunol. 185, 5160–5168 (2010).
Kawaguchi, M. et al. Cytolytic activity of intestinal intraepithelial lymphocytes in germ-free mice is strain dependent and determined by T cells expressing γδ T-cell antigen receptors. Proc. Natl. Acad. Sci. USA 90, 8591–8594 (1993).
Fuss, I.J. et al. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-γ, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J. Immunol. 157, 1261–1270 (1996).
Wehkamp, J. et al. Reduced Paneth cell α-defensins in ileal Crohn's disease. Proc. Natl. Acad. Sci. USA 102, 18129–18134 (2005).
Loftus, E.V. Jr. Clinical epidemiology of inflammatory bowel disease: Incidence, prevalence, and environmental influences. Gastroenterology 126, 1504–1517 (2004).
Amre, D.K. et al. Imbalances in dietary consumption of fatty acids, vegetables, and fruits are associated with risk for Crohn's disease in children. Am. J. Gastroenterol. 102, 2016–2025 (2007).
D'Souza, S. et al. Dietary patterns and risk for Crohn's disease in children. Inflamm. Bowel Dis. 14, 367–373 (2008).
Sousa Guerreiro, C. et al. A comprehensive approach to evaluate nutritional status in Crohn's patients in the era of biologic therapy: a case-control study. Am. J. Gastroenterol. 102, 2551–2556 (2007).
Monteleone, I. et al. Aryl hydrocarbon receptor-induced signals upregulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141, 237–248 (2011).
Kau, A.L., Ahern, P.P., Griffin, N.W., Goodman, A.L. & Gordon, J.I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011).
van den Bogaard, E.H. et al. Coal tar induces AHR-dependent skin barrier repair in atopic dermatitis. J. Clin. Invest. 123, 917–927 (2013).
Lin, T. et al. CD3−CD8+ intestinal intraepithelial lymphocytes (IEL) and the extrathymic development of IEL. Eur. J. Immunol. 24, 1080–1087 (1994).
Rocha, B. The extrathymic T-cell differentiation in the murine gut. Immunol. Rev. 215, 166–177 (2007).
Mora, J.R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003).
Veldhoen, M. & Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat. Rev. Immunol. 12, 696–708 (2012).
Hall, J.A. et al. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor alpha. Immunity 34, 435–447 (2011).
Coombes, J.L. et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β and retinoic acid-dependent mechanism. J. Exp. Med. 204, 1757–1764 (2007).
Hadis, U. et al. Intestinal tolerance requires gut homing and expansion of FoxP3+ regulatory T cells in the lamina propria. Immunity 34, 237–246 (2011).
Sun, C.M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 Treg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).
Takahashi, H. et al. TGF-β and retinoic acid induce the microRNA miR-10a, which targets Bcl-6 and constrains the plasticity of helper T cells. Nat. Immunol. 13, 587–595 (2012).
Benson, M.J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R.J. All-trans retinoic acid mediates enhanced Treg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J. Exp. Med. 204, 1765–1774 (2007).
Elias, K.M. et al. Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway. Blood 111, 1013–1020 (2008).
Hill, J.A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29, 758–770 (2008).
Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).
Mucida, D. et al. Retinoic acid can directly promote TGF-β-mediated Foxp3+ Treg cell conversion of naive T cells. Immunity 30, 471–472, author reply 472–473 (2009).
Brown, C.C. et al. Retinoic acid is essential for Th1 cell lineage stability and prevents transition to a Th17 cell program. Immunity 42, 499–511 (2015).
Pino-Lagos, K. et al. A retinoic acid-dependent checkpoint in the development of CD4+ T cell-mediated immunity. J. Exp. Med. 208, 1767–1775 (2011).
DePaolo, R.W. et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 471, 220–224 (2011).
Bruce, D. & Cantorna, M.T. Intrinsic requirement for the vitamin D receptor in the development of CD8αα-expressing T cells. J. Immunol. 186, 2819–2825 (2011).
Yu, S., Bruce, D., Froicu, M., Weaver, V. & Cantorna, M.T. Failure of T cell homing, reduced CD4/CD8αα intraepithelial lymphocytes, and inflammation in the gut of vitamin D receptor KO mice. Proc. Natl. Acad. Sci. USA 105, 20834–20839 (2008).
Froicu, M. et al. A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. Mol. Endocrinol. 17, 2386–2392 (2003).
Halme, L. et al. Family and twin studies in inflammatory bowel disease. World J. Gastroenterol. 12, 3668–3672 (2006).
Bendik, I., Friedel, A., Roos, F.F., Weber, P. & Eggersdorfer, M. Vitamin D: a critical and essential micronutrient for human health. Front. Physiol. 5, 248 (2014).
Cantorna, M.T. & Mahon, B.D. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp. Biol. Med. 229, 1136–1142 (2004).
Dresner-Pollak, R. et al. The BsmI vitamin D receptor gene polymorphism is associated with ulcerative colitis in Jewish Ashkenazi patients. Genet. Test. 8, 417–420 (2004).
Simmons, J.D., Mullighan, C., Welsh, K.I. & Jewell, D.P. Vitamin D receptor gene polymorphism: association with Crohn's disease susceptibility. Gut 47, 211–214 (2000).
Liu, W. et al. Intestinal epithelial vitamin D receptor signaling inhibits experimental colitis. J. Clin. Invest. 123, 3983–3996 (2013).
Atarashi, K. et al. ATP drives lamina propria TH17 cell differentiation. Nature 455, 808–812 (2008).
Mazmanian, S.K., Liu, C.H., Tzianabos, A.O. & Kasper, D.L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
Torchinsky, M.B., Garaude, J., Martin, A.P. & Blander, J.M. Innate immune recognition of infected apoptotic cells directs TH17 cell differentiation. Nature 458, 78–82 (2009).
Zheng, Y. et al. Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463, 808–812 (2010).
Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Veldhoen, M., Hocking, R.J., Atkins, C.J., Locksley, R.M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).
Narushima, S. et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5, 333–339 (2014).
Obata, Y. et al. The epigenetic regulator Uhrf1 facilitates the proliferation and maturation of colonic regulatory T cells. Nat. Immunol. 15, 571–579 (2014).
Gluckman, P.D., Hanson, M.A., Cooper, C. & Thornburg, K.L. Effect of in utero and early-life conditions on adult health and disease. N. Engl. J. Med. 359, 61–73 (2008).
Sommer, F. & Backhed, F. The gut microbiota–masters of host development and physiology. Nat. Rev. Microbiol. 11, 227–238 (2013).
Turnbaugh, P.J. et al. Organismal, genetic, and transcriptional variation in the deeply sequenced gut microbiomes of identical twins. Proc. Natl. Acad. Sci. USA 107, 7503–7508 (2010).
Turnbaugh, P.J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).
Maynard, C.L., Elson, C.O., Hatton, R.D. & Weaver, C.T. Reciprocal interactions of the intestinal microbiota and immune system. Nature 489, 231–241 (2012).
de Francisco, A. et al. Acute toxicity of vitamin A given with vaccines in infancy. Lancet 342, 526–527 (1993).
Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).
Mora, J.R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).
Mora, J.R., Iwata, M. & von Andrian, U.H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).
Basu, R. et al. Th22 cells are an important source of IL-22 for host protection against enteropathogenic bacteria. Immunity 37, 1061–1075 (2012).
Ramirez, J.M. et al. Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL-22 and IL-17 production by human T helper cells. Eur. J. Immunol. 40, 2450–2459 (2010).
Gagliani, N. et al. TH17 cells transdifferentiate into regulatory T cells during resolution of inflammation. Nature doi:10.1038/nature14452 (29 April 2015).
Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nat. Immunol. 12, 255–263 (2011).
Stockinger, B., Veldhoen, M. & Hirota, K. Modulation of Th17 development and function by activation of the aryl hydrocarbon receptor—the role of endogenous ligands. Eur. J. Immunol. 39, 652–654 (2009).
Hahn, M.E., Karchner, S.I., Shapiro, M.A. & Perera, S.A. Molecular evolution of two vertebrate aryl hydrocarbon (dioxin) receptors (AHR1 and AHR2) and the PAS family. Proc. Natl. Acad. Sci. USA 94, 13743–13748 (1997).
Hahn, M.E. Aryl hydrocarbon receptors: diversity and evolution. Chem. Biol. Interact. 141, 131–160 (2002).
Hahn, M.E. et al. Unexpected diversity of aryl hydrocarbon receptors in non-mammalian vertebrates: insights from comparative genomics. J. Exp. Zoolog. A Comp. Exp. Biol. 305, 693–706 (2006).
Qiu, J. et al. Group 3 innate lymphoid cells inhibit T-cell-mediated intestinal inflammation through aryl hydrocarbon receptor signaling and regulation of microflora. Immunity 39, 386–399 (2013).
Holick, M.F., MacLaughlin, J.A. & Doppelt, S.H. Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator. Science 211, 590–593 (1981).
Bjelakovic, G. et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst. Rev. 1, CD007470 (2014).
Bolland, M.J., Grey, A., Gamble, G.D. & Reid, I.R. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol. 2, 307–320 (2014).
Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).
The authors wish to acknowledge support by the European Research Council fund (ERC) (280307), the European Molecular Biology Organisation (EMBO), and an UK Biotechnology and Biological Sciences Research Council (BBSRC) Institute Strategic Programme (ISP) grant.
The authors declare no competing financial interests.
About this article
Cite this article
Veldhoen, M., Ferreira, C. Influence of nutrient-derived metabolites on lymphocyte immunity. Nat Med 21, 709–718 (2015). https://doi.org/10.1038/nm.3894
International Journal of Molecular Sciences (2021)
Journal of Biological Chemistry (2021)
Impact of Bacterial Metabolites on Gut Barrier Function and Host Immunity: A Focus on Bacterial Metabolism and Its Relevance for Intestinal Inflammation
Frontiers in Immunology (2021)
Journal of Clinical Medicine (2021)
Frontiers in Immunology (2021)