Review Article | Published:

Regulatory T cells in autoimmune disease

Nature Immunologyvolume 19pages665673 (2018) | Download Citation

Abstract

In recent years, the understanding of regulatory T cell (Treg cell) biology has expanded considerably. Key observations have challenged the traditional definition of Treg cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of Treg cell instability, Treg cell plasticity and tissue-specific Treg cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of Treg cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

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

References

  1. 1.

    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).

  2. 2.

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

  3. 3.

    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).

  4. 4.

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

  5. 5.

    Liu, W. et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J. Exp. Med. 203, 1701–1711 (2006).

  6. 6.

    Sakaguchi, S., Miyara, M., Costantino, C. M. & Hafler, D. A. FOXP3+ regulatory T cells in the human immune system. Nat. Rev. Immunol. 10, 490–500 (2010).

  7. 7.

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

  8. 8.

    Kanamori, M., Nakatsukasa, H., Okada, M., Lu, Q. & Yoshimura, A. Induced regulatory T cells: their development, stability, and applications. Trends Immunol. 37, 803–811 (2016).

  9. 9.

    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).

  10. 10.

    Nishizuka, Y. & Sakakura, T. Thymus and reproduction: sex-linked dysgenesia of the gonad after neonatal thymectomy in mice. Science 166, 753–755 (1969).

  11. 11.

    Penhale, W. J., Farmer, A., McKenna, R. P. & Irvine, W. J. Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin. Exp. Immunol. 15, 225–236 (1973).

  12. 12.

    Sakaguchi, S., Takahashi, T. & Nishizuka, Y. Study on cellular events in postthymectomy autoimmune oophoritis in mice. I. Requirement of Lyt-1 effector cells for oocytes damage after adoptive transfer. J. Exp. Med. 156, 1565–1576 (1982).

  13. 13.

    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).

  14. 14.

    Baecher-Allan, C., Brown, J. A., Freeman, G. J. & Hafler, D. A. CD4+CD25high regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001).

  15. 15.

    Stephens, L. A., Mottet, C., Mason, D. & Powrie, F. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur. J. Immunol. 31, 1247–1254 (2001).

  16. 16.

    Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).

  17. 17.

    Miyara, M. et al. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun. Rev. 10, 744–755 (2011).

  18. 18.

    Brusko, T. M., Wasserfall, C. H., Clare-Salzler, M. J., Schatz, D. A. & Atkinson, M. A. Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 54, 1407–1414 (2005).

  19. 19.

    Haseda, F., Imagawa, A., Murase-Mishiba, Y., Terasaki, J. & Hanafusa, T. CD4+ CD45RA FoxP3high activated regulatory T cells are functionally impaired and related to residual insulin-secreting capacity in patients with type 1 diabetes. Clin. Exp. Immunol. 173, 207–216 (2013).

  20. 20.

    Lindley, S. et al. Defective suppressor function in CD4+CD25+ T-cells from patients with type 1 diabetes. Diabetes 54, 92–99 (2005).

  21. 21.

    Dominguez-Villar, M., Baecher-Allan, C. M. & Hafler, D. A. Identification of T helper type 1-like, Foxp3+ regulatory T cells in human autoimmune disease. Nat. Med 17, 673–675 (2011).

  22. 22.

    Viglietta, V., Baecher-Allan, C., Weiner, H. L. & Hafler, D. A. Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J. Exp. Med. 199, 971–979 (2004).

  23. 23.

    Bonelli, M. et al. Quantitative and qualitative deficiencies of regulatory T cells in patients with systemic lupus erythematosus (SLE). Int. Immunol. 20, 861–868 (2008).

  24. 24.

    Thiruppathi, M. et al. Functional defect in regulatory T cells in myasthenia gravis. Ann. NY Acad. Sci. 1274, 68–76 (2012).

  25. 25.

    van Roon, J. A., Hartgring, S. A., van der Wurff-Jacobs, K. M., Bijlsma, J. W. & Lafeber, F. P. Numbers of CD25+Foxp3+ T cells that lack the IL-7 receptor are increased intra-articularly and have impaired suppressive function in RA patients. Rheumatology (Oxford) 49, 2084–2089 (2010).

  26. 26.

    Ohkura, N., Kitagawa, Y. & Sakaguchi, S. Development and maintenance of regulatory T cells. Immunity 38, 414–423 (2013).

  27. 27.

    Arpaia, N. et al. A Distinct function of regulatory T cells in tissue protection. Cell 162, 1078–1089 (2015).

  28. 28.

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

  29. 29.

    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).

  30. 30.

    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).

  31. 31.

    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).

  32. 32.

    Hill, J. A. et al. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 27, 786–800 (2007).

  33. 33.

    Morikawa, H. & Sakaguchi, S. Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol. Rev. 259, 192–205 (2014).

  34. 34.

    Huehn, J. & Beyer, M. Epigenetic and transcriptional control of Foxp3+ regulatory T cells. Semin. Immunol. 27, 10–18 (2015).

  35. 35.

    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).

  36. 36.

    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).

  37. 37.

    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).

  38. 38.

    Baron, U. et al. DNA demethylation in the human FOXP3 locus discriminates regulatory T cells from activated FOXP3(+) conventional T cells. Eur. J. Immunol. 37, 2378–2389 (2007).

  39. 39.

    Floess, S. et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 5, e38 (2007).

  40. 40.

    van Loosdregt, J. et al. Regulation of Treg functionality by acetylation-mediated Foxp3 protein stabilization. Blood 115, 965–974 (2010).

  41. 41.

    Li, B. et al. FOXP3 interactions with histone acetyltransferase and class II histone deacetylases are required for repression. Proc. Natl Acad. Sci. USA 104, 4571–4576 (2007).

  42. 42.

    Beier, U. H., Akimova, T., Liu, Y., Wang, L. & Hancock, W. W. Histone/protein deacetylases control Foxp3 expression and the heat shock response of T-regulatory cells. Curr. Opin. Immunol. 23, 670–678 (2011).

  43. 43.

    Deng, G. et al. Pim-2 kinase influences regulatory T cell function and stability by mediating Foxp3 protein N-terminal phosphorylation. J. Biol. Chem. 290, 20211–20220 (2015).

  44. 44.

    Li, Z. et al. PIM1 kinase phosphorylates the human transcription factor FOXP3 at serine 422 to negatively regulate its activity under inflammation. J. Biol. Chem. 289, 26872–26881 (2014).

  45. 45.

    Morawski, P. A., Mehra, P., Chen, C., Bhatti, T. & Wells, A. D. Foxp3 protein stability is regulated by cyclin-dependent kinase 2. J. Biol. Chem. 288, 24494–24502 (2013).

  46. 46.

    Nie, H. et al. Phosphorylation of FOXP3 controls regulatory T cell function and is inhibited by TNF-α in rheumatoid arthritis. Nat. Med 19, 322–328 (2013).

  47. 47.

    Barbi, J., Pardoll, D. M. & Pan, F. Ubiquitin-dependent regulation of Foxp3 and Treg function. Immunol. Rev. 266, 27–45 (2015).

  48. 48.

    Chen, Z. et al. The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3. Immunity 39, 272–285 (2013).

  49. 49.

    Wang, L. et al. Ubiquitin-specific protease-7 inhibition impairs Tip60-dependent Foxp3+ T-regulatory cell function and promotes antitumor immunity. EBioMedicine 13, 99–112 (2016).

  50. 50.

    Song, X. et al. Structural and biological features of FOXP3 dimerization relevant to regulatory T cell function. Cell Reports 1, 665–675 (2012).

  51. 51.

    Xiao, Y. et al. Dynamic interactions between TIP60 and p300 regulate FOXP3 function through a structural switch defined by a single lysine on TIP60. Cell Rep. 7, 1471–1480 (2014).

  52. 52.

    van Loosdregt, J. et al. Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity. Immunity 39, 259–271 (2013).

  53. 53.

    Dang, E. V. et al. Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146, 772–784 (2011).

  54. 54.

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

  55. 55.

    Samstein, R. M. et al. Foxp3 exploits a pre-existent enhancer landscape for regulatory T cell lineage specification. Cell 151, 153–166 (2012).

  56. 56.

    Kwon, H. K., Chen, H. M., Mathis, D. & Benoist, C. Different molecular complexes that mediate transcriptional induction and repression by FoxP3. Nat. Immunol. 18, 1238–1248 (2017).

  57. 57.

    Tao, R. et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat. Med. 13, 1299–1307 (2007).

  58. 58.

    Bettini, M. L. et al. Loss of epigenetic modification driven by the Foxp3 transcription factor leads to regulatory T cell insufficiency. Immunity 36, 717–730 (2012).

  59. 59.

    Zhang, Y. et al. GP96 is a GARP chaperone and controls regulatory T cell functions. J. Clin. Invest. 125, 859–869 (2015).

  60. 60.

    Bin Dhuban, K. et al. Suppression by human FOXP3+ regulatory T cells requires FOXP3-TIP60 interactions. Sci. Immunol. 2, eaai9297 (2017).

  61. 61.

    Hayatsu, N. et al. Analyses of a mutant Foxp3 allele reveal BATF as a critical transcription factor in the differentiation and accumulation of tissue regulatory T cells. Immunity 47, 268–283 e269 (2017).

  62. 62.

    Darce, J. et al. An N-terminal mutation of the Foxp3 transcription factor alleviates arthritis but exacerbates diabetes. Immunity 36, 731–741 (2012).

  63. 63.

    Wan, Y. Y. & Flavell, R. A. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 445, 766–770 (2007).

  64. 64.

    Williams, L. M. & Rudensky, A. Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat. Immunol. 8, 277–284 (2007).

  65. 65.

    Komatsu, N. et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc. Natl Acad. Sci. USA 106, 1903–1908 (2009).

  66. 66.

    Rubtsov, Y. P. et al. Stability of the regulatory T cell lineage in vivo. Science 329, 1667–1671 (2010).

  67. 67.

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

  68. 68.

    Hoffmann, P. et al. Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation. Eur. J. Immunol. 39, 1088–1097 (2009).

  69. 69.

    Koenen, H. J. et al. Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells. Blood 112, 2340–2352 (2008).

  70. 70.

    Duarte, J. H., Zelenay, S., Bergman, M. L., Martins, A. C. & Demengeot, J. Natural Treg cells spontaneously differentiate into pathogenic helper cells in lymphopenic conditions. Eur. J. Immunol. 39, 948–955 (2009).

  71. 71.

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

  72. 72.

    Laurence, A. et al. STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37, 209–222 (2012).

  73. 73.

    Zhang, Z. et al. Activation and functional specialization of regulatory T cells lead to the generation of Foxp3 instability. J. Immunol. 198, 2612–2625 (2017).

  74. 74.

    Bailey-Bucktrout, S. L. et al. Self-antigen-driven activation induces instability of regulatory T cells during an inflammatory autoimmune response. Immunity 39, 949–962 (2013).

  75. 75.

    Setoguchi, R., Hori, S., Takahashi, T. & Sakaguchi, S. Homeostatic maintenance of natural Foxp3+ CD25+ CD4+ regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J. Exp. Med. 201, 723–735 (2005).

  76. 76.

    Tang, Q. et al. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity 28, 687–697 (2008).

  77. 77.

    Balandina, A., Lécart, S., Dartevelle, P., Saoudi, A. & Berrih-Aknin, S. Functional defect of regulatory CD4+CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 105, 735–741 (2005).

  78. 78.

    Huan, J. et al. Decreased FOXP3 levels in multiple sclerosis patients. J. Neurosci. Res. 81, 45–52 (2005).

  79. 79.

    Long, S. A. et al. Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4+CD25+ regulatory T-cells of type 1 diabetic subjects. Diabetes 59, 407–415 (2010).

  80. 80.

    Zhang, B., Zhang, X., Tang, F., Zhu, L. & Liu, Y. Reduction of forkhead box P3 levels in CD4+CD25high T cells in patients with new-onset systemic lupus erythematosus. Clin. Exp. Immunol. 153, 182–187 (2008).

  81. 81.

    Moes, N. et al. Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy. Gastroenterology 139, 770–778 (2010).

  82. 82.

    Kim, H. J. et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science 350, 334–339 (2015).

  83. 83.

    Nakagawa, H. et al. Instability of Helios-deficient Tregs is associated with conversion to a T-effector phenotype and enhanced antitumor immunity. Proc. Natl Acad. Sci. USA 113, 6248–6253 (2016).

  84. 84.

    Sharma, M. D. et al. An inherently bifunctional subset of Foxp3+ T helper cells is controlled by the transcription factor eos. Immunity 38, 998–1012 (2013).

  85. 85.

    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).

  86. 86.

    Levine, A. G. et al. Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature 546, 421–425 (2017).

  87. 87.

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

  88. 88.

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

  89. 89.

    Bovenschen, H. J. et al. Foxp3+ regulatory T cells of psoriasis patients easily differentiate into IL-17A-producing cells and are found in lesional skin. J. Invest. Dermatol. 131, 1853–1860 (2011).

  90. 90.

    Butcher, M. J. et al. Atherosclerosis-driven Treg plasticity results in formation of a dysfunctional subset of plastic IFNγ+ Th1/Tregs. Circ. Res. 119, 1190–1203 (2016).

  91. 91.

    Kitz, A. et al. AKT isoforms modulate Th1-like Treg generation and function in human autoimmune disease. EMBO Rep. 17, 1169–1183 (2016).

  92. 92.

    Kitz, A. & Dominguez-Villar, M. Molecular mechanisms underlying Th1-like Treg generation and function. Cell. Mol. Life Sci. 74, 4059–4075 (2017).

  93. 93.

    McClymont, S. A. et al. Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J. Immunol. 186, 3918–3926 (2011).

  94. 94.

    Ouyang, W. et al. Novel Foxo1-dependent transcriptional programs control Treg cell function. Nature 491, 554–559 (2012).

  95. 95.

    MacDonald, K. G. et al. Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis. J. Allergy Clin. Immunol. 135, e9 946–e949 (2015).

  96. 96.

    Noval Rivas, M. et al. Regulatory T cell reprogramming toward a Th2-cell-like lineage impairs oral tolerance and promotes food allergy. Immunity 42, 512–523 (2015).

  97. 97.

    Wei, G. et al. Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30, 155–167 (2009).

  98. 98.

    Arterbery, A. S. et al. Production of proinflammatory cytokines by monocytes in liver-transplanted recipients with de novo autoimmune hepatitis is enhanced and induces TH1-like regulatory T cells. J. Immunol. 196, 4040–4051 (2016).

  99. 99.

    Yamada, A. et al. Impaired expansion of regulatory T cells in a neonatal thymectomy-induced autoimmune mouse model. Am. J. Pathol. 185, 2886–2897 (2015).

  100. 100.

    Huynh, A. et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat. Immunol. 16, 188–196 (2015).

  101. 101.

    Shrestha, S. et al. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat. Immunol. 16, 178–187 (2015).

  102. 102.

    Korn, T. et al. Myelin-specific regulatory T cells accumulate in the CNS but fail to control autoimmune inflammation. Nat. Med 13, 423–431 (2007).

  103. 103.

    Tan, T. G., Mathis, D. & Benoist, C. Singular role for T-BET+CXCR3+ regulatory T cells in protection from autoimmune diabetes. Proc. Natl Acad. Sci. USA 113, 14103–14108 (2016).

  104. 104.

    Hernandez, A. L. et al. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. J. Clin. Invest 125, 4212–4222 (2015).

  105. 105.

    Ayyoub, M. et al. Human memory FOXP3+ Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt. Proc. Natl Acad. Sci. USA 106, 8635–8640 (2009).

  106. 106.

    Beriou, G. et al. IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood 113, 4240–4249 (2009).

  107. 107.

    Radhakrishnan, S. et al. Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J. Immunol. 181, 3137–3147 (2008).

  108. 108.

    Singh, K. et al. Reduced CD18 levels drive regulatory T cell conversion into Th17 cells in the CD18hypo PL/J mouse model of psoriasis. J. Immunol. 190, 2544–2553 (2013).

  109. 109.

    Komatsu, N. et al. Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat. Med. 20, 62–68 (2014).

  110. 110.

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

  111. 111.

    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).

  112. 112.

    Kluger, M. A. et al. Stat3 programs Th17-specific regulatory T cells to control GN. J. Am. Soc. Nephrol. 25, 1291–1302 (2014).

  113. 113.

    Kluger, M. A. et al. Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int. 89, 158–166 (2016).

  114. 114.

    Kitani, A. & Xu, L. Regulatory T cells and the induction of IL-17. Mucosal Immunol 1, S43–S46 (2008).

  115. 115.

    Xu, L., Kitani, A., Fuss, I. & Strober, W. Cutting edge: regulatory T cells induce CD4+CD25Foxp3 T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-β. J. Immunol. 178, 6725–6729 (2007).

  116. 116.

    Sharma, M. D. et al. Indoleamine 2,3-dioxygenase controls conversion of Foxp3+ Tregs to TH17-like cells in tumor-draining lymph nodes. Blood 113, 6102–6111 (2009).

  117. 117.

    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).

  118. 118.

    Smith, A. A. et al. Characterization of Th17-like Tregs during late stages of infection with B. pertussis in mice. Possible immunomodulation by type I interferon. J. Immunol. 196, 196.8 (2016).

  119. 119.

    Jin, H. S., Park, Y., Elly, C. & Liu, Y. C. Itch expression by Treg cells controls Th2 inflammatory responses. J. Clin. Invest. 123, 4923–4934 (2013).

  120. 120.

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

  121. 121.

    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).

  122. 122.

    Sanchez Rodriguez, R. et al. Memory regulatory T cells reside in human skin. J. Clin. Invest. 124, 1027–1036 (2014).

  123. 123.

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

  124. 124.

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

  125. 125.

    Hamaguchi, M. & Sakaguchi, S. Regulatory T cells expressing PPAR-γ control inflammation in obesity. Cell Metab. 16, 4–6 (2012).

  126. 126.

    Kasheta, M. et al. Identification and characterization of Treg-like cells in zebrafish. J. Exp. Med. 214, 3519–3530 (2017).

  127. 127.

    Hui, S. P. et al. Zebrafish regulatory T cells mediate organ-specific regenerative programs. Dev. Cell 43, 659–672 (2017).

  128. 128.

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

  129. 129.

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

  130. 130.

    Yu, X., Huang, Q. & Petersen, F. History and milestones of mouse models of autoimmune diseases. Curr. Pharm. Des. 21, 2308–2319 (2015).

  131. 131.

    Bluestone, J. A. et al. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci. Transl. Med. 7, 315ra189 (2015).

  132. 132.

    Desreumaux, P. et al. Safety and efficacy of antigen-specific regulatory T-cell therapy for patients with refractory Crohn's disease. Gastroenterology 143, 1207–1217 (2012).

  133. 133.

    Marek-Trzonkowska, N. et al. Therapy of type 1 diabetes with CD4+CD25highCD127 regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin. Immunol. 153, 23–30 (2014).

  134. 134.

    Marek-Trzonkowska, N. et al. Administration of CD4+CD25highCD127 regulatory T cells preserves β-cell function in type 1 diabetes in children. Diabetes Care 35, 1817–1820 (2012).

  135. 135.

    Dawson, N. A. J. & Levings, M. K. Antigen-specific regulatory T cells: are police CARs the answer? Transl. Res. 187, 53–58 (2017).

Download references

Acknowledgements

We thank members of the Hafler and Dominguez-Villar laboratories for critical reading of the manuscript.

Author information

Affiliations

  1. Department of Neurology, Yale School of Medicine, New Haven, CN, USA

    • Margarita Dominguez-Villar
    •  & David A. Hafler
  2. Department of Immunobiology, Yale School of Medicine, New Haven, CN, USA

    • David A. Hafler

Authors

  1. Search for Margarita Dominguez-Villar in:

  2. Search for David A. Hafler in:

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Margarita Dominguez-Villar or David A. Hafler.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41590-018-0120-4