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Development and maintenance of intestinal regulatory T cells

Key Points

  • Intestinal regulatory T (Treg) cells consist of at least three subpopulations: IL-10+RORγt+ microbiota-stimulated peripherally derived Treg (pTreg) cells, RORγt−NRP1− dietary antigen-stimulated pTreg cells and GATA3+ thymus-derived Treg (tTreg) cells.

  • Treg cell subpopulations have complementary functions, including the maintenance of homeostasis against the microbiota and dietary components in the steady state and the suppression of inflammatory responses.

  • The gut microbiota influences the differentiation, accumulation, function and T cell receptor (TCR) repertoire of colonic Treg cells. In turn, the host–microbiota symbiotic relationship in the gut relies on Treg cells that control antigen-specific responses directed to gut microorganisms.

  • Microbial and dietary metabolites, such as short-chain fatty acids, vitamins and amino acids affect the differentiation and the survival of Treg cells.

  • Treg cell generation involves several mechanisms that function in a cell-intrinsic and cell-extrinsic manner. Macrophages, innate lymphoid cells and dendritic cells are strategically positioned beneath the intestinal epithelial cells to sense the types and the features of the intraluminal microorganisms and dietary components and to coordinately promote T cell homeostasis in the intestines.

Abstract

Gut-resident forkhead box P3 (FOXP3)+CD4+ regulatory T cells (Treg cells) are distinct from those in other organs and have gut-specific phenotypes and functions. Whereas Treg cells in other organs have T cell receptors (TCRs) specific for self antigens, intestinal Treg cells have a distinct set of TCRs that are specific for intestinal antigens, and these cells have pivotal roles in the suppression of immune responses against harmless dietary antigens and commensal microorganisms. The differentiation, migration and maintenance of intestinal Treg cells are controlled by specific signals from the local environment. In particular, certain members of the microbiota continuously provide antigens and immunoregulatory small molecules that modulate intestinal Treg cells. Understanding the development and the maintenance of intestinal Treg cells provides important insights into disease-relevant host–microorganism interactions.

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Figure 1: Stepwise induction of tTreg cells and pTreg cells.
Figure 2: Proposed mechanisms for the accumulation of colonic Treg cells.
Figure 3: Three subpopulations in the intestinal Treg cells.
Figure 4: Cellular and molecular mechanisms for the induction of intestinal pTreg cells.

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References

  1. Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Maloy, K. J. & Powrie, F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature 474, 298–306 (2011).

    Article  CAS  PubMed  Google Scholar 

  3. Sakaguchi, S., Sakaguchi, N., Asano, M., Itoh, M. & Toda, M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor α-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J. Immunol. 155, 1151–1164 (1995).

    CAS  PubMed  Google Scholar 

  4. Mottet, C., Uhlig, H. H. & Powrie, F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J. Immunol. 170, 3939–3943 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  PubMed  Google Scholar 

  6. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Brunkow, M. E. et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat. Genet. 27, 68–73 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Lahl, K. et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J. Exp. Med. 204, 57–63 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22, 329–341 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Mayer, C. T. et al. Few Foxp3+ regulatory T cells are sufficient to protect adult mice from lethal autoimmunity. Eur. J. Immunol. 44, 2990–3002 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. Chatila, T. A. et al. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J. Clin. Invest. 106, R75–R81 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Wildin, R. S. et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat. Genet. 27, 18–20 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Langer, L. F., Clay, T. M. & Morse, M. A. Update on anti-CTLA-4 antibodies in clinical trials. Expert Opin. Biol. Ther. 7, 1245–1256 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Groux, H. et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 389, 737–742 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Okamura, T. et al. TGF-β3-expressing CD4+CD25−LAG3+ regulatory T cells control humoral immune responses. Nat. Commun. 6, 6329 (2015).

    Article  CAS  PubMed  Google Scholar 

  19. Round, J. L. & Mazmanian, S. K. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc. Natl Acad. Sci. USA 107, 12204–12209 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Weiss, J. M. et al. Neuropilin 1 is expressed on thymus-derived natural regulatory T cells, but not mucosa-generated induced Foxp3+ T reg cells. J. Exp. Med. 209, 1723–42 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Collison, L. W. et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450, 566–569 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Li, M. O., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26, 579–591 (2007).

    Article  CAS  PubMed  Google Scholar 

  26. Rubtsov, Y. P. et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28, 546–558 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Wing, K. et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science 322, 271–275 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Zheng, Y. et al. Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control TH2 responses. Nature 458, 351–356 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Herman, A. E., Freeman, G. J., Mathis, D. & Benoist, C. CD4+CD25+ T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion. J. Exp. Med. 199, 1479–1489 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kawamoto, S. et al. Foxp3+ T cells regulate immunoglobulin a selection and facilitate diversification of bacterial species responsible for immune homeostasis. Immunity 41, 152–165 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Cong, Y., Feng, T., Fujihashi, K., Schoeb, T. R. & Elson, C. O. A dominant, coordinated T regulatory cell-IgA response to the intestinal microbiota. Proc. Natl Acad. Sci. USA 106, 19256–19261 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Maloy, K. J. et al. CD4+CD25+ TR cells suppress innate immune pathology through cytokine-dependent mechanisms. J. Exp. Med. 197, 111–119 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Kim, S. V. et al. GPR15-mediated homing controls immune homeostasis in the large intestine mucosa. Science 340, 1456–1459 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013). References 19–21 and 34 show that commensal Clostridia and Bacteroides species can promote the accumulation of colonic T reg cells.

    Article  CAS  PubMed  Google Scholar 

  35. Kim, K. S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–663 (2016). This paper shows that a substantial proportion of the T reg cell population in the small intestines is induced by dietary antigens.

    Article  CAS  PubMed  Google Scholar 

  36. Curotto de Lafaille, M. A. & Lafaille, J. J. Natural and adaptive foxp3+ regulatory T cells: more of the same or a division of labor? Immunity 30, 626–635 (2009).

    Article  CAS  PubMed  Google Scholar 

  37. Curotto de Lafaille, M. A. et al. Adaptive Foxp3+ regulatory T cell-dependent and -independent control of allergic inflammation. Immunity 29, 114–126 (2008).

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. 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 

  40. Haribhai, D. et al. A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity. Immunity 35, 109–122 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Thornton, A. M. et al. Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J. Immunol. 184, 3433–3441 (2010). This paper was the first to define Helios as a potential marker to distinguish pT reg cells and tT reg cells.

    Article  CAS  PubMed  Google Scholar 

  42. Yadav, M. et al. Neuropilin-1 distinguishes natural and inducible regulatory T cells among regulatory T cell subsets in vivo. J. Exp. Med. 209, 1713–1722 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gottschalk, R. A., Corse, E. & Allison, J. P. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J. Immunol. 188, 976–980 (2012).

    Article  CAS  PubMed  Google Scholar 

  44. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Tone, Y. et al. Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nat. Immunol. 9, 194–202 (2008).

    Article  CAS  PubMed  Google Scholar 

  46. Xu, L. et al. Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I. Immunity 33, 313–325 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Josefowicz, S. Z. et al. Extrathymically generated regulatory T cells control mucosal TH2 inflammation. Nature 482, 395–399 (2012). This paper shows that pT reg cells function to actively suppress mucosal T H 2-type inflammation at mucosal sites.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Lathrop, S. K. et al. Peripheral education of the immune system by colonic commensal microbiota. Nature 478, 250–254 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cebula, A. et al. Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature 497, 258–262 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Korn, L. L. et al. Regulatory T cells occupy an isolated niche in the intestine that is antigen independent. Cell Rep. 9, 1567–1573 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Nishio, J. et al. Requirement of full TCR repertoire for regulatory T cells to maintain intestinal homeostasis. Proc. Natl Acad. Sci. USA 112, 12770–12775 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Feuerer, M. et al. Genomic definition of multiple ex vivo regulatory T cell subphenotypes. Proc. Natl Acad. Sci. USA 107, 5919–5924 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Miyara, M. et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 30, 899–911 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Murai, M., Krause, P., Cheroutre, H. & Kronenberg, M. Regulatory T-cell stability and plasticity in mucosal and systemic immune systems. Mucosal Immunol. 3, 443–449 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tsuji, M. et al. Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer's patches. Science 323, 1488–1492 (2009).

    Article  CAS  PubMed  Google Scholar 

  56. Ohkura, N. et al. T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37, 785–799 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Morikawa, H. et al. Differential roles of epigenetic changes and Foxp3 expression in regulatory T cell-specific transcriptional regulation. Proc. Natl Acad. Sci. USA 111, 5289–5294 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ono, M. et al. Foxp3 controls regulatory T-cell function by interacting with AML1/Runx1. Nature 446, 685–689 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Feng, Y. et al. Control of the inheritance of regulatory T cell identity by a cis element in the Foxp3 locus. Cell 158, 749–763 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, X., Liang, Y., LeBlanc, M., Benner, C. & Zheng, Y. Function of a Foxp3 cis-element in protecting regulatory T cell identity. Cell 158, 734–748 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yang, B. H. et al. Foxp3 T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol. 9, 444–457 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Sakaguchi, S., Vignali, D. A., Rudensky, A. Y., Niec, R. E. & Waldmann, H. The plasticity and stability of regulatory T cells. Nat. Rev. Immunol. 13, 461–467 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Miyao, T. et al. Plasticity of Foxp3+ T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36, 262–275 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Koch, M. A. et al. The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat. Immunol. 10, 595–602 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Wohlfert, E. A. et al. GATA3 controls Foxp3+ regulatory T cell fate during inflammation in mice. J. Clin. Invest. 121, 4503–4515 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rudra, D. et al. Transcription factor Foxp3 and its protein partners form a complex regulatory network. Nat. Immunol. 13, 1010–1019 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yu, F., Sharma, S., Edwards, J., Feigenbaum, L. & Zhu, J. Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat. Immunol. 16, 197–206 (2015).

    Article  CAS  PubMed  Google Scholar 

  68. Chung, Y. et al. Follicular regulatory T cells expressing Foxp3 and Bcl-6 suppress germinal center reactions. Nat. Med. 17, 983–988 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lochner, M. et al. Restricted microbiota and absence of cognate TCR antigen leads to an unbalanced generation of Th17 cells. J. Immunol. 186, 1531–1537 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Ohnmacht, C. et al. The microbiota regulates type 2 immunity through RORγt+ T cells. Science 349, 989–993 (2015).

    Article  CAS  PubMed  Google Scholar 

  71. Sefik, E. et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349, 993–997 (2015). References 61, 70 and 71 show that a subset of intestinal T reg cells express RORγt and that their development is modulated by the microbiota.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Schiering, C. et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 513, 564–568 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Griseri, T., Asquith, M., Thompson, C. & Powrie, F. OX40 is required for regulatory T cell-mediated control of colitis. J. Exp. Med. 207, 699–709 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Liston, A. & Gray, D. H. Homeostatic control of regulatory T cell diversity. Nat. Rev. Immunol. 14, 154–165 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Levine, A. G., Arvey, A., Jin, W. & Rudensky, A. Y. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15, 1070–1078 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Cretney, E. et al. The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat. Immunol. 12, 304–311 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3− precursor cells in the absence of interleukin 10. Nat. Immunol. 8, 931–941 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Kamanaka, M. et al. Expression of interleukin-10 in intestinal lymphocytes detected by an interleukin-10 reporter knockin tiger mouse. Immunity 25, 941–952 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Takeda, K. et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10, 39–49 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Huber, S. et al. Th17 cells express interleukin-10 receptor and are controlled by Foxp3− and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner. Immunity 34, 554–565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Park, S. G. et al. T regulatory cells maintain intestinal homeostasis by suppressing γδ T cells. Immunity 33, 791–803 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Marson, A. et al. Foxp3 occupancy and regulation of key target genes during T-cell stimulation. Nature 445, 931–935 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chaudhry, A. et al. Interleukin-10 signaling in regulatory T cells is required for suppression of Th17 cell-mediated inflammation. Immunity 34, 566–578 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Itoh, K. & Mitsuoka, T. Characterization of clostridia isolated from faeces of limited flora mice and their effect on caecal size when associated with germ-free mice. Lab Anim. 19, 111–118 (1985).

    Article  CAS  PubMed  Google Scholar 

  86. Sokol, H. et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc. Natl Acad. Sci. USA 105, 16731–16736 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sarrabayrouse, G. et al. CD4CD8αα lymphocytes, a novel human regulatory T cell subset induced by colonic bacteria and deficient in patients with inflammatory bowel disease. PLoS Biol. 12, e1001833 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Narushima, S. et al. Characterization of the 17 strains of regulatory T cell-inducing human-derived Clostridia. Gut Microbes 5, 333–339 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  CAS  PubMed  Google Scholar 

  90. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

    Article  CAS  PubMed  Google Scholar 

  91. Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013). References 89, 90 and 91 identify SCFAs as strong inducers of colonic T reg cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Di Giacinto, C., Marinaro, M., Sanchez, M., Strober, W. & Boirivant, M. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGFβ-bearing regulatory cells. J. Immunol. 174, 3237–3246 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Karimi, K., Inman, M. D., Bienenstock, J. & Forsythe, P. Lactobacillus reuteri-induced regulatory T cells protect against an allergic airway response in mice. Am. J. Respir. Crit. Care Med. 179, 186–193 (2009).

    Article  CAS  PubMed  Google Scholar 

  94. Tang, C. et al. Inhibition of dectin-1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe 18, 183–197 (2015).

    Article  CAS  PubMed  Google Scholar 

  95. Shen, Y. et al. Outer membrane vesicles of a human commensal mediate immune regulation and disease protection. Cell Host Microbe 12, 509–520 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Faith, J. J., Ahern, P. P., Ridaura, V. K., Cheng, J. & Gordon, J. I. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci. Transl Med. 6, 220ra11 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Mucida, D. et al. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317, 256–260 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Kang, S. G., Lim, H. W., Andrisani, O. M., Broxmeyer, H. E. & Kim, C. H. Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J. Immunol. 179, 3724–3733 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. 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 

  100. 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 

  101. 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 

  102. Yamaguchi, T. et al. Control of immune responses by antigen-specific regulatory T cells expressing the folate receptor. Immunity 27, 145–159 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Kinoshita, M. et al. Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J. Immunol. 189, 2869–2878 (2012).

    Article  CAS  PubMed  Google Scholar 

  104. Mezrich, J. D. et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J. Immunol. 185, 3190–3198 (2010).

    Article  CAS  PubMed  Google Scholar 

  105. Wang, J. et al. Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35. J. Biol. Chem. 281, 22021–22028 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zandi-Nejad, K. et al. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J. 27, 4366–4374 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Farache, J. et al. Luminal bacteria recruit CD103+ dendritic cells into the intestinal epithelium to sample bacterial antigens for presentation. Immunity 38, 581–595 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. 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 

  111. Hickey, C. A. et al. Colitogenic Bacteroides thetaiotaomicron antigens access host immune cells in a sulfatase-dependent manner via outer membrane vesicles. Cell Host Microbe 17, 672–680 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Travis, M. A. et al. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Persson, E. K. et al. IRF4 transcription-factor-dependent CD103+CD11b+ dendritic cells drive mucosal T helper 17 cell differentiation. Immunity 38, 958–969 (2013).

    Article  CAS  PubMed  Google Scholar 

  115. Schlitzer, A. et al. IRF4 transcription factor-dependent CD11b+ dendritic cells in human and mouse control mucosal IL-17 cytokine responses. Immunity 38, 970–983 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Welty, N. E. et al. Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J. Exp. Med. 210, 2011–2024 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Edelson, B. T. et al. Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells. J. Exp. Med. 207, 823–836 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Ginhoux, F. et al. The origin and development of nonlymphoid tissue CD103+ DCs. J. Exp. Med. 206, 3115–3130 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Manicassamy, S. et al. Activation of β-catenin in dendritic cells regulates immunity versus tolerance in the intestine. Science 329, 849–853 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Mosconi, I. et al. Intestinal bacteria induce TSLP to promote mutualistic T-cell responses. Mucosal Immunol. 6, 1157–1167 (2013).

    Article  CAS  PubMed  Google Scholar 

  121. Rimoldi, M. et al. Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat. Immunol. 6, 507–514 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. 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 

  124. Honda, K. & Littman, D. R. The microbiome in infectious disease and inflammation. Annu. Rev. Immunol. 30, 759–795 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. van Nood, E. et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N. Engl. J. Med. 368, 407–415 (2013). This randomized study shows the high therapeutic efficacy of FMT for C. difficile infection.

    Article  CAS  PubMed  Google Scholar 

  126. Kump, P. K. et al. Alteration of intestinal dysbiosis by fecal microbiota transplantation does not induce remission in patients with chronic active ulcerative colitis. Inflamm. Bowel Dis. 19, 2155–2165 (2013).

    Article  PubMed  Google Scholar 

  127. Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl Med. 7, 307ra152 (2015).

    Article  PubMed  CAS  Google Scholar 

  129. Miyake, S. et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS ONE 10, e0137429 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Kashiwagi, I. et al. Smad2 and Smad3 inversely regulate TGF-β autoinduction in Clostridium butyricum-activated dendritic cells. Immunity 43, 65–79 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Hayashi, A. et al. A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe 13, 711–722 (2013).

    Article  CAS  PubMed  Google Scholar 

  132. Calcinaro, F. et al. Oral probiotic administration induces interleukin-10 production and prevents spontaneous autoimmune diabetes in the non-obese diabetic mouse. Diabetologia 48, 1565–1575 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Li, Y. N. et al. Effect of oral feeding with Clostridium leptum on regulatory T-cell responses and allergic airway inflammation in mice. Ann. Allergy Asthma Immunol. 109, 201–207 (2012).

    Article  CAS  PubMed  Google Scholar 

  134. Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Dasgupta, S., Erturk-Hasdemir, D., Ochoa-Reparaz, J., Reinecker, H. C. & Kasper, D. L. Plasmacytoid dendritic cells mediate anti-inflammatory responses to a gut commensal molecule via both innate and adaptive mechanisms. Cell Host Microbe 15, 413–423 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Jang, S. O. et al. Asthma prevention by Lactobacillus Rhamnosus in a mouse model is associated with CD4+CD25+Foxp3+ T Cells. Allergy Asthma Immunol. Res. 4, 150–156 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Lavasani, S. et al. A novel probiotic mixture exerts a therapeutic effect on experimental autoimmune encephalomyelitis mediated by IL-10 producing regulatory T cells. PLoS ONE 5, e9009 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Wang, S. et al. MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43, 289–303 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  139. Kunisawa, J., Hashimoto, E., Ishikawa, I. & Kiyono, H. A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS ONE 7, e32094 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by CREST and the Practical Research Project for Intractable Diseases from the Japan Agency for Medical Research and Development (AMED), the Suzuken Memorial Foundation, the Nakajima Foundation, the Takeda Science Foundation, the Mishima Kaiun Memorial Foundation, Keio University Medical Science Fund and the Uehara Memorial Foundation.

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Correspondence to Kenya Honda.

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Glossary

DEREG mice

(Depletion of regulatory T cells mice). Transgenic mice expressing a diphtheria toxin receptor under the control of the forkhead box P3 (Foxp3) gene promoter, using a bacterial artificial chromosome. Administration of diphtheria toxin to these mice results in the conditional deletion of FOXP3+ regulatory T cells.

Foxp3GFP mice

Mice expressing a chimeric GFP–forkhead box P3 (FOXP3) fusion protein from the Foxp3 locus. All FOXP3+ regulatory T cells in these mice express GFP. Note that the modified Foxp3 allele functions as a genetic susceptibility locus.

Immunodysregulation, polyendocrinopathy, enteropathy X-linked syndrome

(IPEX syndrome). A primary immunodeficiency caused by mutations in forkhead box P3 (FOXP3). Patients with this syndrome have defective functional regulatory T cells and develop insulin-dependent diabetes, thyroiditis, eczema, haemolytic anaemia and inflammatory bowel disease. In the absence of a bone marrow transplant, these patients die at an early age.

T follicular helper cell

(TFH cell). A CD4+ T helper cell lineage that is essential for the induction of class switching in the germinal centres of secondary lymphoid follicles during antibody responses to T cell-dependent antigens. These cells support the differentiation of antigen-specific B cells into memory B cells or plasma cells.

Germ-free mice

Mice that are completely free of the presence of other organisms. Germ-free mice are produced by hysterectomy rederivation and must be maintained in sterile isolators under very strict handling procedures to keep them germ-free.

Antibiotic-treated mice

A generally accessible alternative to using germ-free mice in which the microbiota of conventional mice is depleted by using a combination of broad-spectrum antibiotics. A combination of ampicillin, vancomycin, neomycin and metronidazol is frequently used for this purpose. However, any antibiotic treatment protocol tested so far achieves only an incomplete depletion of the microbiota.

Specific pathogen-free mice

(SPF mice). Mice that harbour a complex diversity of commensal microorganisms but are free of a specific list of organisms. The list of organisms typically includes disease-causing pathogens that can affect mouse health and research outcomes, as well as opportunistic organisms (pathobionts) that typically do not cause illness in normal, healthy mice.

Keratin 14-transgenic mice

(K14-transgenic mice). Mice that are generated by crossing mice lacking all MHC class II-associated molecules with transgenic mice in which these molecules are expressed under the control of the keratin promoter. In these mice, MHC class II-associated antigens are expressed solely by epidermal cells and cortical thymic epithelial cells.

T regulatory type 1 cells

(TR1 cells). A subset of forkhead box P3 (FOXP3)−CD4+ regulatory T cells that secrete high levels of interleukin-10 (IL-10). TR1 cells were originally described as a subset of naive CD4+ T cells activated ex vivo in the presence of IL-10 or by IL-10-conditioned dendritic cells. TR1 cells mediate suppression by a cell contact-independent, cytokine- dependent mechanism that involves IL-10 and transforming growth factor-β.

CD4+CD8αα+ regulatory T cells

Unlike most T cells in the periphery, a substantial fraction of intestinal mucosal T cells express the homodimeric form of CD8 (CD8αα), together with CD4. CD4+CD8αα+ T cells show regulatory characteristics and secrete interleukin-10. These cells have an oligoclonal T cell receptor repertoire directed towards intestinal commensal bacteria and their frequency is decreased in germ-free mice and in patients with inflammatory bowel disease.

Altered Schaedler flora

(ASF). A standard enteric flora that were selected for their dominance and persistence in the normal microflora of mice. ASF contains eight species. The 16S gene sequence of ASF360 is identical to Lactobacillus acidophilus, whereas that of ASF361 is similar to that of Lactobacillus murinus and Lactobacillus animalis. ASF519 is related to Bacteroides distasonis, whereas ASF356, ASF502 and ASF492 fall within Clostridia cluster XIV. ASF457 is a spiral-shaped bacterium that clusters with the Flexistipes species, whereas ASF500 is not closely related to any of the sequences in the database.

Outer membrane vesicles

(OMVs). Spherical buds of the outer membrane filled with periplasmic content produced by Gram-negative bacteria. The production of OMVs allows bacteria to interact with their environment, thereby having an important role in bacterial physiology as well as in virulence and commensalism. As commensal bacteria generally do not make intimate contact with host cells, OMVs appear to provide a suitable mechanism for members of the microbiota to deliver molecules to the host.

Dysbiosis

A condition with imbalance in the composition of the bacterial microbiota; this includes an outgrowth of potentially pathogenic bacteria and/or a decrease in bacterial diversity and bacteria beneficial to the host.

Faecal microbiota transplantation

(FMT). A process of transplantation of a diverse intestinal microbial community from a healthy individual into a patient through infusion of stool by orogastric tube, enema, colonoscopy or oral administration of a capsule containing freeze-dried material.

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Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat Rev Immunol 16, 295–309 (2016). https://doi.org/10.1038/nri.2016.36

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