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  • Review Article
  • Published:

Dietary influences on intestinal immunity

Key Points

  • Epidemiological studies associate the rapid increase in the incidence of inflammatory disorders with a 'Western lifestyle', and especially with the 'Western diet' that is characterized by processed foods and a low content of vegetables and fruits.

  • Shared molecular pathways between nutrient- and pathogen-sensing systems provide a potential molecular link between diet and disease. Targets at the intersection of metabolic and inflammatory responses are ligand-activated nuclear receptors and G protein-coupled receptors.

  • Vitamins A and D (both acting through nuclear receptors) alter lymphocyte migration and activation, thereby contributing to intestinal immune homeostasis, which is characterized by a state of tolerance towards innocuous antigens.

  • Plants of the Brassica genus, which includes cruciferous vegetables such as green cabbages and broccoli, contain ligands for the nuclear receptor aryl hydrocarbon receptor (AHR). AHR activity is required for the maintenance of intraepithelial lymphocytes and the proliferative capacity of postnatally developed RORγt+ innate lymphoid cells in the intestine.

  • Fatty acids activate G protein-coupled receptors (namely GPR120 and GPR40) and nuclear receptors (namely PPARs, LXRs and FXR) that are expressed by immune cells. Saturated fatty acids are generally thought to have a role in promoting inflammation, whereas unsaturated fatty acids have both pro-inflammatory and anti-inflammatory properties.

  • Dietary metabolites directly act on immune cells involved in the development, organization and function of the intestine, with wider implications for other organs. A balanced diet contributes to immune homeostasis, preventing aberrant immunity and pathology.

Abstract

The function of the gastrointestinal tract relies on a monolayer of epithelial cells, which are essential for the uptake of nutrients. The fragile lining requires protection against insults by a diverse array of antigens. This is accomplished by the mucosa-associated lymphoid tissues of the gastrointestinal tract, which constitute a highly organized immune organ. In this Review, we discuss several recent findings that provide a compelling link between dietary compounds and the organization and maintenance of immune tissues and lymphocytes in the intestine. We highlight some of the molecular players involved, in particular ligand-activated nuclear receptors in lymphoid cells.

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Figure 1: The molecular and cellular mechanisms of action of vitamin A.
Figure 2: The molecular and cellular mechanisms of action of vitamin D.
Figure 3: The molecular and cellular mechanisms of action of AHR ligands and dietary lipids.
Figure 4: The cellular network in intestinal homeostasis and inflammation.

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References

  1. Eder, W., Ege, M. J. & von Mutius, E. The asthma epidemic. N. Engl. J. Med. 355, 2226–2235 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Maslowski, K. M. & Mackay, C. R. Diet, gut microbiota and immune responses. Nature Immunol. 12, 5–9 (2011). This article gives an insight into the diet–microbiota model as the basis for the greater incidence of asthma and autoimmunity in developed countries.

    Article  CAS  Google Scholar 

  3. Bach, J. F. The effect of infections on susceptibility to autoimmune and allergic diseases. N. Engl. J. Med. 347, 911–920 (2002).

    Article  PubMed  Google Scholar 

  4. Devereux, G. The increase in the prevalence of asthma and allergy: food for thought. Nature Rev. Immunol. 6, 869–874 (2006).

    Article  CAS  Google Scholar 

  5. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  CAS  PubMed  Google Scholar 

  7. Macia, L. et al. Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases. Immunol. Rev. 245, 164–176 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Glass, C. K. & Ogawa, S. Combinatorial roles of nuclear receptors in inflammation and immunity. Nature Rev. Immunol. 6, 44–55 (2006).

    Article  Google Scholar 

  9. Zygmunt, B. & Veldhoen, M. T helper cell differentiation: more than just cytokines. Adv. Immunol. 109, 159–196 (2011).

    Article  CAS  PubMed  Google Scholar 

  10. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, W. et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Lochner, M. et al. In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORγt+ T cells. J. Exp. Med. 205, 1381–1393 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhou, L. et al. TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt function. Nature 453, 236–240 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Esplugues, E. et al. Control of TH17 cells occurs in the small intestine. Nature 475, 514–518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. O'Connor, W. Jr., Zenewicz, L. A. & Flavell, R. A. The dual nature of TH17 cells: shifting the focus to function. Nature Immunol. 11, 471–476 (2010).

    Article  CAS  Google Scholar 

  19. Zhou, X. et al. Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nature Immunol. 10, 1000–1007 (2009).

    Article  CAS  Google Scholar 

  20. Ogawa, A., Andoh, A., Araki, Y., Bamba, T. & Fujiyama, Y. Neutralization of interleukin-17 aggravates dextran sulfate sodium-induced colitis in mice. Clin. Immunol. 110, 55–62 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Monticelli, L. A., Sonnenberg, G. F. & Artis, D. Innate lymphoid cells: critical regulators of allergic inflammation and tissue repair in the lung. Curr. Opin. Immunol. 24, 284–289 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eberl, G. & Littman, D. R. The role of the nuclear hormone receptor RORγt in the development of lymph nodes and Peyer's patches. Immunol. Rev. 195, 81–90 (2003).

    Article  CAS  PubMed  Google Scholar 

  23. Zenewicz, L. A. et al. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity 29, 947–957 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Veldhoen, M. et al. The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453, 106–109 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Yang, X. O. et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity 28, 29–39 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Deeb, K. K., Trump, D. L. & Johnson, C. S. Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nature Rev. Cancer 7, 684–700 (2007).

    Article  CAS  Google Scholar 

  27. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nature Rev. Immunol. 8, 685–698 (2008).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. Sun, C. M. et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J. Exp. Med. 204, 1775–1785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to 'program' T cell attraction to the epidermal chemokine CCL27. Nature Immunol. 8, 285–293 (2007).

    Article  CAS  Google Scholar 

  34. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007). This is the first description of retinoic acid as a modulator of T H 17 cell and T Reg cell development.

    Article  CAS  PubMed  Google Scholar 

  35. 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. Nature Immunol. 13, 587–595 (2012).

    Article  CAS  Google Scholar 

  36. Benson, M. J., Pino-Lagos, K., Rosemblatt, M. & Noelle, R. J. 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. 204, 1765–1774 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hill, J. A. et al. Retinoic acid enhances Foxp3 induction indirectly by relieving inhibition from CD4+CD44hi cells. Immunity 29, 758–770 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Meseguer, S., Mudduluru, G., Escamilla, J. M., Allgayer, H. & Barettino, D. Micro-RNAs-10a and -10b contribute to retinoic acid-induced differentiation of neuroblastoma cells and target the alternative splicing regulatory factor SFRS1 (SF2/ASF). J. Biol. Chem. 286, 4150–4164 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hall, J. A. et al. Essential role for retinoic acid in the promotion of CD4+ T cell effector responses via retinoic acid receptor α. Immunity 34, 435–447 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Nurieva, R. I. et al. Bcl6 mediates the development of T follicular helper cells. Science 325, 1001–1005 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hirota, K. et al. Fate mapping of IL-17-producing T cells in inflammatory responses. Nature Immunol. 12, 255–263 (2011).

    Article  CAS  Google Scholar 

  43. Xiao, S. et al. Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-β-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J. Immunol. 181, 2277–2284 (2008). This study showed the molecular mechanisms by which retinoic acid affects both T Reg cell and T H 17 cell differentiation.

    Article  CAS  PubMed  Google Scholar 

  44. Kang, S. W. et al. 1,25-dihyroxyvitamin D3 promotes FOXP3 expression via binding to vitamin D response elements in its conserved noncoding sequence region. J. Immunol. 188, 5276–5282 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature 424, 88–93 (2003). References 31 and 45 first identified a role for retinoic acid-producing DCs in promoting T cell homing to the intestine.

    Article  CAS  PubMed  Google Scholar 

  46. Johansson-Lindbom, B. et al. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J. Exp. Med. 202, 1063–1073 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mora, J. R. et al. Generation of gut-homing IgA-secreting B cells by intestinal dendritic cells. Science 314, 1157–1160 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Wang, N. S. et al. Divergent transcriptional programming of class-specific B cell memory by T-bet and RORα. Nature Immunol. 13, 604–611 (2012).

    Article  CAS  Google Scholar 

  49. Worm, M., Krah, J. M., Manz, R. A. & Henz, B. M. Retinoic acid inhibits CD40+ interleukin-4-mediated IgE production in vitro. Blood 92, 1713–1720 (1998).

    CAS  PubMed  Google Scholar 

  50. Jeffery, L. E. et al. 1,25-dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183, 5458–5467 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. von Essen, M. R. et al. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunol. 11, 344–349 (2010).

    Article  CAS  Google Scholar 

  52. D'Ambrosio, D. et al. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. J. Clin. Invest. 101, 252–262 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Penna, G. & Adorini, L. 1 α,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405–2411 (2000).

    Article  CAS  PubMed  Google Scholar 

  54. Gorman, S. et al. Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. J. Immunol. 179, 6273–6283 (2007).

    Article  CAS  PubMed  Google Scholar 

  55. Chang, J. H., Cha, H. R., Lee, D. S., Seo, K. Y. & Kweon, M. N. 1,25-dihydroxyvitamin D3 inhibits the differentiation and migration of TH17 cells to protect against experimental autoimmune encephalomyelitis. PLoS ONE 5, e12925 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Hirota, K. et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Reboldi, A. et al. C-C chemokine receptor 6-regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE. Nature Immunol. 10, 514–523 (2009).

    Article  CAS  Google Scholar 

  58. 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).

    Article  CAS  PubMed  Google Scholar 

  59. Konkel, J. E. et al. Control of the development of CD8αα+ intestinal intraepithelial lymphocytes by TGF-β. Nature Immunol. 12, 312–319 (2011).

    Article  CAS  Google Scholar 

  60. Quintana, F. J. et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453, 65–71 (2008). References 24 and 60 provide the first demonstration that AHR, through the sensing of external cues, has a role in T H 17 cell and T Reg cell biology.

    Article  CAS  PubMed  Google Scholar 

  61. Kiss, E. A. et al. Natural aryl hydrocarbon receptor ligands control organogenesis of intestinal lymphoid follicles. Science 334, 1561–1565 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. 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. Nature Immunol. 13, 144–151 (2011).

    Article  CAS  Google Scholar 

  63. Qiu, J. et al. The aryl hydrocarbon receptor regulates gut immunity through modulation of innate lymphoid cells. Immunity 36, 92–104 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li, Y. et al. Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147, 629–640 (2011). References 61 and 64 identified diet-derived AHR ligands as crucial factors in the development and maintenance of gut-associated lymphoid cells and tissues.

    Article  CAS  PubMed  Google Scholar 

  65. Wincent, E. et al. The suggested physiologic aryl hydrocarbon receptor activator and cytochrome P4501 substrate 6-formylindolo[3,2-b]carbazole is present in humans. J. Biol. Chem. 284, 2690–2696 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Knoop, K. A. & Newberry, R. D. Isolated lymphoid follicles are dynamic reservoirs for the induction of intestinal IgA. Front. Immunol. 3, 84 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Shi, H. et al. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015–3025 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Solinas, G., Naugler, W., Galimi, F., Lee, M. S. & Karin, M. Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates. Proc. Natl Acad. Sci. USA 103, 16454–16459 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wang, J., Wu, X., Simonavicius, N., Tian, H. & Ling, L. Medium-chain fatty acids as ligands for orphan G protein-coupled receptor GPR84. J. Biol. Chem. 281, 34457–34464 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Hirasawa, A. et al. Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120. Nature Med. 11, 90–94 (2005). This was the first study to demonstrate that the G protein-coupled receptor GPR120 functions as a receptor for unsaturated long-chain free fatty acids.

    Article  CAS  PubMed  Google Scholar 

  72. Oh, D. Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Itoh, Y. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  74. Liou, A. P. et al. The G-protein-coupled receptor GPR40 directly mediates long-chain fatty acid-induced secretion of cholecystokinin. Gastroenterology 140, 903–912 (2011).

  75. 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).

    Article  CAS  PubMed  Google Scholar 

  76. Nyirenda, M. H. et al. TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J. Immunol. 187, 2278–2290 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Oberg, H. H. et al. Differential but direct abolishment of human regulatory T cell suppressive capacity by various TLR2 ligands. J. Immunol. 184, 4733–4740 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Reynolds, J. M. et al. Toll-like receptor 2 signaling in CD4+ T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease. Immunity 32, 692–702 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Sutmuller, R. P. et al. Toll-like receptor 2 controls expansion and function of regulatory T cells. J. Clin. Invest. 116, 485–494 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Forman, B. M., Umesono, K., Chen, J. & Evans, R. M. Unique response pathways are established by allosteric interactions among nuclear hormone receptors. Cell 81, 541–550 (1995).

    Article  CAS  PubMed  Google Scholar 

  81. Kliewer, S. A. et al. A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation. Cell 83, 813–819 (1995). References 80 and 81 first showed that fatty acid metabolites interact with PPARγ.

    Article  CAS  PubMed  Google Scholar 

  82. Clark, R. B. et al. The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses. J. Immunol. 164, 1364–1371 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Dunn, S. E. et al. Peroxisome proliferator-activated receptor δ limits the expansion of pathogenic Th cells during central nervous system autoimmunity. J. Exp. Med. 207, 1599–1608 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Faveeuw, C. et al. Peroxisome proliferator-activated receptor γ activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett. 486, 261–266 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Li, B., Reynolds, J. M., Stout, R. D., Bernlohr, D. A. & Suttles, J. Regulation of Th17 differentiation by epidermal fatty acid-binding protein. J. Immunol. 182, 7625–7633 (2009).

    Article  CAS  PubMed  Google Scholar 

  86. Wang, L. H. et al. Transcriptional inactivation of STAT3 by PPARγ suppresses IL-6-responsive multiple myeloma cells. Immunity 20, 205–218 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Klotz, L. et al. The nuclear receptor PPARγ selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J. Exp. Med. 206, 2079–2089 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature Med. 15, 930–939 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Janowski, B. A. et al. Structural requirements of ligands for the oxysterol liver X receptors LXRα and LXRβ. Proc. Natl Acad. Sci. USA 96, 266–271 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Makishima, M. et al. Identification of a nuclear receptor for bile acids. Science 284, 1362–1365 (1999).

    Article  CAS  PubMed  Google Scholar 

  92. Vavassori, P., Mencarelli, A., Renga, B., Distrutti, E. & Fiorucci, S. The bile acid receptor FXR is a modulator of intestinal innate immunity. J. Immunol. 183, 6251–6261 (2009).

    Article  CAS  PubMed  Google Scholar 

  93. Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J. & Tontonoz, P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nature Med. 9, 213–219 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. A-Gonzalez, N et al. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity 31, 245–258 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Bensinger, S. J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97–111 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Cui, G. et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J. Clin. Invest. 121, 658–670 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kallen, J. A. et al. X-ray structure of the hRORα LBD at 1.63 A: structural and functional data that cholesterol or a cholesterol derivative is the natural ligand of RORα. Structure 10, 1697–1707 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Boismenu, R. & Havran, W. L. Modulation of epithelial cell growth by intraepithelial γδ T cells. Science 266, 1253–1255 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Ismail, A. S. et al. γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface. Proc. Natl Acad. Sci. USA 108, 8743–8748 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  100. 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).

    Article  CAS  PubMed  Google Scholar 

  101. Hou, J. K., Abraham, B. & El-Serag, H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am. J. Gastroenterol. 106, 563–573 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Arnson, Y., Amital, H. & Shoenfeld, Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann. Rheum. Dis. 66, 1137–1142 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Lochner, M. et al. Microbiota-induced tertiary lymphoid tissues aggravate inflammatory disease in the absence of RORγt and LTi cells. J. Exp. Med. 208, 125–134 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sherlock, J. P. et al. IL-23 induces spondyloarthropathy by acting on ROR-γt+ CD3+CD4CD8 entheseal resident T cells. Nature Med. 18, 1069–1076 (2012).

    Article  CAS  PubMed  Google Scholar 

  105. Lawrence, T., Willoughby, D. A. & Gilroy, D. W. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nature Rev. Immunol. 2, 787–795 (2002).

    Article  CAS  Google Scholar 

  106. Kliewer, S. A. et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proc. Natl Acad. Sci. USA 94, 4318–4323 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Kumar, S. Molecular clocks: four decades of evolution. Nature Rev. Genet. 6, 654–662 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Cordain, L. et al. Origins and evolution of the Western diet: health implications for the 21st century. Am. J. Clin. Nutr. 81, 341–354 (2005). This review explains how our nutritional characteristics have changed through time.

    Article  CAS  PubMed  Google Scholar 

  109. Willett, W. C. Balancing life-style and genomics research for disease prevention. Science 296, 695–698 (2002).

    Article  CAS  PubMed  Google Scholar 

  110. Cerf-Bensussan, N. & Gaboriau-Routhiau, V. The immune system and the gut microbiota: friends or foes? Nature Rev. Immunol. 10, 735–744 (2010).

    Article  CAS  Google Scholar 

  111. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol. 10, 159–169 (2010).

    Article  CAS  Google Scholar 

  112. McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Cherrier, M. & Eberl, G. The development of LTi cells. Curr. Opin. Immunol. 24, 178–183 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

    Article  CAS  PubMed  Google Scholar 

  115. Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Veldhoen, M., Hocking, R. J., Flavell, R. A. & Stockinger, B. Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nature Immunol. 7, 1151–1156 (2006).

    Article  CAS  Google Scholar 

  117. Yu, D. et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31, 457–468 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Wong, S. H. et al. Transcription factor RORα is critical for nuocyte development. Nature Immunol. 13, 229–236 (2012).

    Article  CAS  Google Scholar 

  121. Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nature Immunol. 5, 64–73 (2004).

    Article  CAS  Google Scholar 

  122. Sonnenberg, G. F., Fouser, L. A. & Artis, D. Border patrol: regulation of immunity, inflammation and tissue homeostasis at barrier surfaces by IL-22. Nature Immunol. 12, 383–390 (2011).

    Article  CAS  Google Scholar 

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Acknowledgements

V.B.-W. is supported by the Deutsche Forschungsgemeinschaft (DFG BR 4253/1-1 Forschungsstipendium). M.V. is supported by a UK Biotechnology and Biological Sciences Research Council Institute Strategic Programme Grant and the European Research Council (grant number 280307: Epithelial_Immunol).

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Glossary

Nuclear receptors

A class of proteins found within cells that are responsible for sensing external cues (such as hormones) and that work with other proteins to regulate the expression of specific genes, thereby controlling the development, homeostasis and metabolism of the organism.

ILCs

Lymphoid cells derived from the common lymphoid progenitor that lack expression of an antigen receptor. ILCs have important roles in innate immune responses to infectious microorganisms and in lymphoid tissue formation.

PPARs

A group of nuclear receptor proteins involved in altering lipid and glucose metabolism. Their ligands include free fatty acids and eicosanoids.

LXRs

A group of nuclear receptor proteins important in regulating cholesterol, fatty acid and glucose homeostasis. A ligand is oxysterol.

FXR

A member of the nuclear receptor family of transcription factors, with a role in maintaining bile acid, cholesterol and glucose homeostasis. Bile acids are natural ligands.

Lamina propria

Connective tissue beneath the intestinal epithelium containing various myeloid and lymphoid cells.

IELs

A T cell population found within the epithelial layer of mammalian mucosal linings. This population consists of specialized subsets of cells, such as particular γδ T cell subsets and αβ CD8αα+ T cells.

Cytochrome P450 enzymes

A superfamily of diverse enzymes involved in drug metabolism and bioactivation, accounting for a very large number of different metabolic reactions, including those for lipids, hormones and xenobiotics (such as drugs and chemicals).

γδ T cells

A small subset of T cells that express a distinct T cell receptor on their surface consisting of a particular γ-chain, which correlates with their presence in particular tissues, coupled to a δ-chain.

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Veldhoen, M., Brucklacher-Waldert, V. Dietary influences on intestinal immunity. Nat Rev Immunol 12, 696–708 (2012). https://doi.org/10.1038/nri3299

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