Review Article | Published:

Regulatory T cell adaptation in the intestine and skin


The intestine and skin are distinct microenvironments with unique physiological functions and are continually exposed to diverse environmental challenges. Host adaptation at these sites is an active process that involves interaction between immune cells and tissue cells. Regulatory T cells (Treg cells) play a pivotal role in enforcing homeostasis at barrier surfaces, illustrated by the development of intestinal and skin inflammation in diseases caused by primary deficiency in Treg cells. Treg cells at barrier sites are phenotypically distinct from their lymphoid-organ counterparts, and these ‘tissue’ signatures often reflect their tissue-adapted function. We discuss current understanding of Treg cell adaptation in the intestine and skin, including unique phenotypes, functions and metabolic demands, and how increased knowledge of Treg cells at barrier sites might guide precision medicine therapies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Sakaguchi, S., Fukuma, K., Kuribayashi, K. & Masuda, T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161, 72–87 (1985).

  2. 2.

    Powrie, F. & Mason, D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J. Exp. Med. 172, 1701–1708 (1990).

  3. 3.

    Sakaguchi, S., Yamaguchi, T., Nomura, T. & Ono, M. Regulatory T cells and immune tolerance. Cell 133, 775–787 (2008).

  4. 4.

    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).

  5. 5.

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

  6. 6.

    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).

  7. 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).

  8. 8.

    Josefowicz, S. Z., Lu, L.-F. & Rudensky, A. Y. Regulatory T cells: mechanisms of differentiation and function. Annu. Rev. Immunol. 30, 531–564 (2012).

  9. 9.

    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).

  10. 10.

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

  11. 11.

    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).

  12. 12.

    Gambineri, E., Torgerson, T. R. & Ochs, H. D. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr. Opin. Rheumatol. 15, 430–435 (2003).

  13. 13.

    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).

  14. 14.

    Powrie, F., Leach, M. W., Mauze, S., Caddle, L. B. & Coffman, R. L. Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int. Immunol. 5, 1461–1471 (1993).

  15. 15.

    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).

  16. 16.

    Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013).

  17. 17.

    Panduro, M., Benoist, C. & Mathis, D. Tissue Tregs. Annu. Rev. Immunol. 34, 609–633 (2016).

  18. 18.

    Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016).

  19. 19.

    Ali, N. & Rosenblum, M. D. Regulatory T cells in skin. Immunology 152, 372–381 (2017).

  20. 20.

    Nutsch, K. et al. Rapid and efficient generation of regulatory T cells to commensal antigens in the periphery. Cell Reports 17, 206–220 (2016).

  21. 21.

    Russler-Germain, E. V., Rengarajan, S. & Hsieh, C. S. Antigen-specific regulatory T-cell responses to intestinal microbiota. Mucosal Immunol. 10, 1375–1386 (2017).

  22. 22.

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

  23. 23.

    Chai, J. N. et al. Helicobacter species are potent drivers of colonic T cell responses in homeostasis and inflammation. Sci. Immunol. 2, eaal5068 (2017).

  24. 24.

    Xu, M. et al. c-MAF-dependent regulatory T cells mediate immunological tolerance to a gut pathobiont. Nature 554, 373–377 (2018).

  25. 25.

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

  26. 26.

    Hegazy, A. N. et al. Circulating and tissue-resident CD4+ T cells with reactivity to intestinal microbiota are abundant in healthy individuals and function is altered during inflammation. Gastroenterology 153, 1320–1337.e16 (2017).

  27. 27.

    Verma, R. et al. Cell surface polysaccharides of Bifidobacterium bifidum induce the generation of Foxp3+ regulatory T cells. Sci. Immunol. 3, eaat6975 (2018).

  28. 28.

    Wei, S., Kryczek, I. & Zou, W. Regulatory T-cell compartmentalization and trafficking. Blood 108, 426–431 (2006).

  29. 29.

    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).

  30. 30.

    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).

  31. 31.

    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).

  32. 32.

    Miragaia, R.J. et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 50, 493–504.e7 (2019).

  33. 33.

    Tomura, M. et al. Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice. J. Clin. Invest. 120, 883–893 (2010).

  34. 34.

    Cretney, E., Kallies, A. & Nutt, S. L. Differentiation and function of Foxp3+ effector regulatory T cells. Trends Immunol. 34, 74–80 (2013).

  35. 35.

    Vasanthakumar, A. et al. The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat. Immunol. 16, 276–285 (2015).

  36. 36.

    Li, C. et al. TCR transgenic mice reveal stepwise, multi-site acquisition of the distinctive fat-Treg phenotype. Cell 174, 285–299.e12 (2018).

  37. 37.

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

  38. 38.

    Wang, Y., Su, M. A. & Wan, Y. Y. An essential role of the transcription factor GATA-3 for the function of regulatory T cells. Immunity 35, 337–348 (2011).

  39. 39.

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

  40. 40.

    Sefik, E. et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science 349, 993–997 (2015).

  41. 41.

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

  42. 42.

    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).

  43. 43.

    Torgerson, T. R. et al. Severe food allergy as a variant of IPEX syndrome caused by a deletion in a noncoding region of the FOXP3 gene. Gastroenterology 132, 1705–1717 (2007).

  44. 44.

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

  45. 45.

    Campbell, C. et al. Extrathymically generated regulatory T cells establish a niche for intestinal border-dwelling bacteria and affect physiologic metabolite balance. Immunity 48, 1245–1257.e9 (2018).

  46. 46.

    Kim, K. S. et al. Dietary antigens limit mucosal immunity by inducing regulatory T cells in the small intestine. Science 351, 858–863 (2016).

  47. 47.

    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).

  48. 48.

    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).

  49. 49.

    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).

  50. 50.

    Zhang, C. et al. ‘Repair’ Treg cells in tissue injury. Cell. Physiol. Biochem. 43, 2155–2169 (2017).

  51. 51.

    Siede, J. et al. IL-33 receptor-expressing regulatory T cells are highly activated, TH2 biased and suppress CD4 T cell proliferation through IL-10 and TGFβ release. PLoS One 11, e0161507 (2016).

  52. 52.

    Belkaid, Y. & Tarbell, K. Regulatory T cells in the control of host-microorganism interactions (*). Annu. Rev. Immunol. 27, 551–589 (2009).

  53. 53.

    Wang, Z. et al. Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium. Mucosal Immunol. 7, 1290–1301 (2014).

  54. 54.

    Pandiyan, P., Zheng, L., Ishihara, S., Reed, J. & Lenardo, M. J. CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat. Immunol. 8, 1353–1362 (2007).

  55. 55.

    Biton, M. et al. T Helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320.e22 (2018).

  56. 56.

    Oldenhove, G. et al. Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31, 772–786 (2009).

  57. 57.

    Edwards, J. P. et al. The GARP/Latent TGF-β1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance. Eur. J. Immunol. 46, 1480–1489 (2016).

  58. 58.

    Konkel, J. E. & Chen, W. Balancing acts: the role of TGF-β in the mucosal immune system. Trends Mol. Med. 17, 668–676 (2011).

  59. 59.

    Worthington, J. J., Czajkowska, B. I., Melton, A. C. & Travis, M. A. Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3+ regulatory T cells via integrin αvβ8. Gastroenterology 141, 1802–1812 (2011).

  60. 60.

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

  61. 61.

    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).

  62. 62.

    Schlenner, S. M., Weigmann, B., Ruan, Q., Chen, Y. & von Boehmer, H. Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. J. Exp. Med. 209, 1529–1535 (2012).

  63. 63.

    Konkel, J. E. et al. Transforming growth factor-β signaling in regulatory T cells controls T helper-17 cells and tissue-specific immune responses. Immunity 46, 660–674 (2017).

  64. 64.

    Zúñiga, L. A., Jain, R., Haines, C. & Cua, D. J. Th17 cell development: from the cradle to the grave. Immunol. Rev. 252, 78–88 (2013).

  65. 65.

    Izcue, A. et al. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis. Immunity 28, 559–570 (2008).

  66. 66.

    Gabryšová, L. et al. c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells. Nat. Immunol. 19, 497–507 (2018).

  67. 67.

    Saraiva, M. & O’Garra, A. The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10, 170–181 (2010).

  68. 68.

    Pichery, M. et al. Endogenous IL-33 is highly expressed in mouse epithelial barrier tissues, lymphoid organs, brain, embryos, and inflamed tissues: in situ analysis using a novel Il-33-LacZ gene trap reporter strain. J. Immunol. 188, 3488–3495 (2012).

  69. 69.

    Fan, X. & Rudensky, A. Y. Hallmarks of tissue-resident lymphocytes. Cell 164, 1198–1211 (2016).

  70. 70.

    Vasanthakumar, A. et al. The TNF receptor superfamily-NF-κB axis is critical to maintain effector regulatory T cells in lymphoid and non-lymphoid tissues. Cell Reports 20, 2906–2920 (2017).

  71. 71.

    Salomon, B. L. et al. Tumor necrosis factor α and regulatory T cells in oncoimmunology. Front. Immunol. 9, 444 (2018).

  72. 72.

    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).

  73. 73.

    Long, M., Park, S. G., Strickland, I., Hayden, M. S. & Ghosh, S. Nuclear factor-κB modulates regulatory T cell development by directly regulating expression of Foxp3 transcription factor. Immunity 31, 921–931 (2009).

  74. 74.

    Schuster, M. et al. IκB(NS) protein mediates regulatory T cell development via induction of the Foxp3 transcription factor. Immunity 37, 998–1008 (2012).

  75. 75.

    Ye, J. et al. The aryl hydrocarbon receptor preferentially marks and promotes gut regulatory T cells. Cell Reports 21, 2277–2290 (2017).

  76. 76.

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

  77. 77.

    Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013).

  78. 78.

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

  79. 79.

    Kullberg, M. C. et al. Bacteria-triggered CD4+ T regulatory cells suppress Helicobacter hepaticus-induced colitis. J. Exp. Med. 196, 505–515 (2002).

  80. 80.

    Bilate, A. M. et al. Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor. Sci. Immunol. 1, eaaf7471 (2016).

  81. 81.

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

  82. 82.

    Yang, Y. et al. Focused specificity of intestinal TH17 cells towards commensal bacterial antigens. Nature 510, 152–156 (2014).

  83. 83.

    Kolodin, D. et al. Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. Cell Metab. 21, 543–557 (2015).

  84. 84.

    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).

  85. 85.

    Danne, C. et al. A Large Polysaccharide Produced by Helicobacter hepaticus Induces an Anti-inflammatory Gene Signature in Macrophages. Cell Host Microbe 22, 733–745.e5 (2017).

  86. 86.

    Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

  87. 87.

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).

  88. 88.

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

  89. 89.

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

  90. 90.

    Maslowski, K. M. et al. Regulation of inflammatory responses by gut microbiota and chemoattractant receptor GPR43. Nature 461, 1282–1286 (2009).

  91. 91.

    Hamer, H. M. et al. Review article: the role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2008).

  92. 92.

    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).

  93. 93.

    Shinde, R. & McGaha, T. L. The aryl hydrocarbon receptor: connecting immunity to the microenvironment. Trends Immunol. 39, 1005–1020 (2018).

  94. 94.

    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).

  95. 95.

    Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403–432 (2014).

  96. 96.

    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).

  97. 97.

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

  98. 98.

    Annacker, O. et al. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J. Exp. Med. 202, 1051–1061 (2005).

  99. 99.

    Travis, M. A. et al. Loss of integrin αVβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449, 361–365 (2007).

  100. 100.

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

  101. 101.

    Povoleri, G. A. M. et al. Human retinoic acid-regulated CD161+ regulatory T cells support wound repair in intestinal mucosa. Nat. Immunol. 19, 1403–1414 (2018).

  102. 102.

    Ikeda, K. et al. Slc3a2 mediates branched-chain amino-acid-dependent maintenance of regulatory T cells. Cell Reports 21, 1824–1838 (2017).

  103. 103.

    Yamazaki, S. et al. Homeostasis of thymus-derived Foxp3+ regulatory T cells is controlled by ultraviolet B exposure in the skin. J. Immunol. 193, 5488–5497 (2014).

  104. 104.

    Delacher, M. et al. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat. Immunol. 18, 1160–1172 (2017).

  105. 105.

    Malhotra, N. et al. RORα-expressing T regulatory cells restrain allergic skin inflammation. Sci. Immunol. 3, eaao6923 (2018).

  106. 106.

    Harrison, O. J. et al. Commensal-specific T cell plasticity promotes rapid tissue adaptation to injury. Science 363, eaat6280 (2018).

  107. 107.

    Halabi-Tawil, M. et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br. J. Dermatol. 160, 645–651 (2009).

  108. 108.

    Scharschmidt, T. C. et al. A wave of regulatory T cells into neonatal skin mediates tolerance to commensal microbes. Immunity 43, 1011–1021 (2015).

  109. 109.

    Belkaid, Y., Piccirillo, C. A., Mendez, S., Shevach, E. M. & Sacks, D. L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420, 502–507 (2002).

  110. 110.

    Nosbaum, A. et al. Cutting edge: regulatory T cells facilitate cutaneous wound healing. J. Immunol. 196, 2010–2014 (2016).

  111. 111.

    Stockenhuber, K. et al. Foxp3+ Treg cells control psoriasiform inflammation by restraining an IFN-I-driven CD8+ T cell response. J. Exp. Med. 215, 1987–1998 (2018).

  112. 112.

    Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129.e11 (2017).

  113. 113.

    Seneschal, J., Clark, R. A., Gehad, A., Baecher-Allan, C. M. & Kupper, T. S. Human epidermal Langerhans cells maintain immune homeostasis in skin by activating skin resident regulatory T cells. Immunity 36, 873–884 (2012).

  114. 114.

    Clark, R. A. & Kupper, T. S. IL-15 and dermal fibroblasts induce proliferation of natural regulatory T cells isolated from human skin. Blood 109, 194–202 (2007).

  115. 115.

    Gratz, I. K. et al. Cutting edge: memory regulatory T cells require IL-7 and not IL-2 for their maintenance in peripheral tissues. J. Immunol. 190, 4483–4487 (2013).

  116. 116.

    Gajardo, T., Morales, R. A., Campos-Mora, M., Campos-Acuña, J. & Pino-Lagos, K. Exogenous interleukin-33 targets myeloid-derived suppressor cells and generates periphery-induced Foxp3+ regulatory T cells in skin-transplanted mice. Immunology 146, 81–88 (2015).

  117. 117.

    Leichner, T. M. et al. Skin-derived TSLP systemically expands regulatory T cells. J. Autoimmun. 79, 39–52 (2017).

  118. 118.

    Grice, E. A. et al. Topographical and temporal diversity of the human skin microbiome. Science 324, 1190–1192 (2009).

  119. 119.

    Chen, Y. E., Fischbach, M. A. & Belkaid, Y. Skin microbiota-host interactions. Nature 553, 427–436 (2018).

  120. 120.

    Scharschmidt, T. C. et al. Commensal microbes and hair follicle morphogenesis coordinately drive Treg migration into neonatal skin. Cell Host Microbe 21, 467–477.e5 (2017).

  121. 121.

    Naik, S. et al. Compartmentalized control of skin immunity by resident commensals. Science 337, 1115–1119 (2012).

  122. 122.

    Guilliams, M. et al. Skin-draining lymph nodes contain dermis-derived CD103 dendritic cells that constitutively produce retinoic acid and induce Foxp3+ regulatory T cells. Blood 115, 1958–1968 (2010).

  123. 123.

    Galimberti, F. & Mesinkovska, N. A. Skin findings associated with nutritional deficiencies. Cleve. Clin. J. Med. 83, 731–739 (2016).

  124. 124.

    Sanford, J. A. et al. Inhibition of HDAC8 and HDAC9 by microbial short-chain fatty acids breaks immune tolerance of the epidermis to TLR ligands. Sci. Immunol. 1, eaah4609 (2016).

  125. 125.

    Magiatis, P. et al. Malassezia yeasts produce a collection of exceptionally potent activators of the Ah (dioxin) receptor detected in diseased human skin. J. Invest. Dermatol. 133, 2023–2030 (2013).

  126. 126.

    Schwarz, T. 25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells. Photochem. Photobiol. 84, 10–18 (2008).

  127. 127.

    Yamazaki, S. et al. Ultraviolet B-induced maturation of CD11b-type Langerin dendritic cells controls the expansion of Foxp3+ regulatory T cells in the skin. J. Immunol. 200, 119–129 (2018).

  128. 128.

    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).

  129. 129.

    van der Aar, A. M. et al. Vitamin D3 targets epidermal and dermal dendritic cells for induction of distinct regulatory T cells. J. Allergy Clin. Immunol. 127, 1532–40.e7 (2011).

  130. 130.

    Newton, R., Priyadharshini, B. & Turka, L. A. Immunometabolism of regulatory T cells. Nat. Immunol. 17, 618–625 (2016).

  131. 131.

    Zeng, H. et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function. Nature 499, 485–490 (2013).

  132. 132.

    Kabat, A. M. et al. The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5, e12444 (2016).

  133. 133.

    Michalek, R. D. et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J. Immunol. 186, 3299–3303 (2011).

  134. 134.

    Gerriets, V. A. et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J. Clin. Invest. 125, 194–207 (2015).

  135. 135.

    Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).

  136. 136.

    Santori, F. R. et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 21, 286–298 (2015).

  137. 137.

    Howie, D. et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight 2, e89160 (2017).

  138. 138.

    Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293.e7 (2017).

  139. 139.

    Klysz, D. et al. Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal. 8, ra97 (2015).

  140. 140.

    Pollizzi, K. N. & Powell, J. D. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat. Rev. Immunol. 14, 435–446 (2014).

  141. 141.

    Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277–285 (2016).

  142. 142.

    Read, S., Malmström, V. & Powrie, F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25+CD4+ regulatory cells that control intestinal inflammation. J. Exp. Med. 192, 295–302 (2000).

  143. 143.

    Gupta, A., De Felice, K. M., Loftus, E. V. Jr. & Khanna, S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment. Pharmacol. Ther. 42, 406–417 (2015).

  144. 144.

    Barnes, M. J. & Powrie, F. Regulatory T cells reinforce intestinal homeostasis. Immunity 31, 401–411 (2009).

  145. 145.

    Uhlig, H. H. & Powrie, F. Translating immunology into therapeutic concepts for inflammatory bowel disease. Annu. Rev. Immunol. 36, 755–781 (2018).

  146. 146.

    Edwards, J. P., Thornton, A. M. & Shevach, E. M. Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. J. Immunol. 193, 2843–2849 (2014).

  147. 147.

    Salem, M. et al. GARP dampens cancer immunity by sustaining function and accumulation of regulatory T cells in the colon. Cancer Res. (2019).

  148. 148.

    Worthington, J. J. et al. Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Immunity 42, 903–915 (2015).

  149. 149.

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

  150. 150.

    Schmidt, A., Oberle, N. & Krammer, P. H. Molecular mechanisms of Treg-mediated T cell suppression. Front. Immunol. 3, 51 (2012).

Download references

Author information

Competing interests

The authors declare no competing interests.

Correspondence to Fiona Powrie.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Treg cell development and subsets in the intestine and skin.
Fig. 2: Host and environmental pathways that shape intestinal Treg cells.
Fig. 3: Treg cell functions in the intestine and skin.
Fig. 4: Host and environmental pathways that shape skin Treg cells.
Fig. 5: Model for the metabolic adaptation of Treg cells at barrier sites.