Regulatory T cells in the treatment of disease

Abstract

Regulatory T (Treg) cells suppress inflammation and regulate immune system activity. In patients with systemic or organ-specific autoimmune diseases or those receiving transplanted organs, Treg cells are compromised. Approaches to strengthen Treg cell function, either by expanding them ex vivo and reinfusing them or by increasing the number or capacity of existing Treg cells, have entered clinical trials. Unlike the situation in autoimmunity, in patients with cancer, Treg cells limit the antitumour immune response and promote angiogenesis and tumour growth. Their immunosuppressive function may, in part, explain the failure of many immunotherapies in cancer. Strategies to reduce the function and/or number of Treg cells specifically in tumour sites are being investigated to promote antitumour immunity and regression. Here, we describe the current progress in modulating Treg cells in autoimmune disorders, transplantation and cancer.

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Figure 1: Steps in Treg cell development in vivo and in vitro.
Figure 2: Therapeutic approaches to alter Treg cells in autoimmune diseases and transplantation.
Figure 3: The production of therapeutic Treg cells.

References

  1. 1

    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).

  2. 2

    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).

  3. 3

    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).

  4. 4

    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).

  5. 5

    June, C. H. Adoptive T cell therapy for cancer in the clinic. J. Clin. Invest. 117, 1466–1476 (2007).

  6. 6

    Hoffmann, P. et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol. Blood Marrow Transplant. 12, 267–274 (2006).

  7. 7

    Wright, G. P. et al. Adoptive therapy with redirected primary regulatory T cells results in antigen-specific suppression of arthritis. Proc. Natl Acad. Sci. USA 106, 19078–19083 (2009).

  8. 8

    Matsuoka, K. et al. Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci. Transl Med. 5, 179ra43 (2013).

  9. 9

    Saadoun, D. et al. Regulatory T cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N. Engl. J. Med. 365, 2067–2077 (2011). This is one of the first studies to show that low-dose IL-2 can produce clinical benefit by expanding T reg cells.

  10. 10

    Klatzmann, D. & Abbas, A. K. The promise of low-dose interleukin-2 therapy for autoimmune and inflammatory diseases. Nat. Rev. Immunol. 15, 283–294 (2015).

  11. 11

    Jonuleit, H. et al. Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J. Exp. Med. 193, 1285–1294 (2001).

  12. 12

    Piccirillo, C. A. & Shevach, E. M. Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin. Immunol. 16, 81–88 (2004).

  13. 13

    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).

  14. 14

    Morgan, M. E. et al. Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans. Hum. Immunol. 66, 13–20 (2005).

  15. 15

    Gavin, M. A. et al. Single-cell analysis of normal and FOXP3-mutant human T cells: FOXP3 expression without regulatory T cell development. Proc. Natl Acad. Sci. USA 103, 6659–6664 (2006).

  16. 16

    Allan, S. E. et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int. Immunol. 19, 345–354 (2007).

  17. 17

    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).

  18. 18

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

  19. 19

    Omenetti, S. & Pizarro, T. T. The Treg/Th17 axis: a dynamic balance regulated by the gut microbiome. Front. Immunol. 6, 639 (2015).

  20. 20

    Lio, C. W. & Hsieh, C. S. A two-step process for thymic regulatory T cell development. Immunity 28, 100–111 (2008).

  21. 21

    Burchill, M. A. et al. Linked T cell receptor and cytokine signaling govern the development of the regulatory T cell repertoire. Immunity 28, 112–121 (2008).

  22. 22

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

  23. 23

    Luo, C. T. & Li, M. O. Transcriptional control of regulatory T cell development and function. Trends Immunol. 34, 531–539 (2013).

  24. 24

    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).

  25. 25

    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).

  26. 26

    Mahmud, S. A. et al. Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells. Nat. Immunol. 15, 473–481 (2014).

  27. 27

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

  28. 28

    Marie, J. C., Liggitt, D. & Rudensky, A. Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-beta receptor. Immunity 25, 441–454 (2006).

  29. 29

    Konkel, J. E., Jin, W., Abbatiello, B., Grainger, J. R. & Chen, W. Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proc. Natl Acad. Sci. USA 111, E465–E473 (2014).

  30. 30

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

  31. 31

    Chen, W. & Konkel, J. E. Development of thymic Foxp3(+) regulatory T cells: TGF-β matters. Eur. J. Immunol. 45, 958–965 (2015).

  32. 32

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

  33. 33

    Qureshi, O. S. et al. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332, 600–603 (2011).

  34. 34

    Liang, B. et al. Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J. Immunol. 180, 5916–5926 (2008).

  35. 35

    Sarris, M., Andersen, K. G., Randow, F., Mayr, L. & Betz, A. G. Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition. Immunity 28, 402–413 (2008).

  36. 36

    Borsellino, G. et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110, 1225–1232 (2007).

  37. 37

    Kobie, J. J. et al. T regulatory and primed uncommitted CD4 T cells express CD73, which suppresses effector CD4 T cells by converting 5′-adenosine monophosphate to adenosine. J. Immunol. 177, 6780–6786 (2006).

  38. 38

    Deaglio, S. et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J. Exp. Med. 204, 1257–1265 (2007).

  39. 39

    Chinen, T. et al. An essential role for the IL-2 receptor in Treg cell function. Nat. Immunol. 17, 1322–1333 (2016).

  40. 40

    Malek, T. R. et al. IL-2 family of cytokines in T regulatory cell development and homeostasis. J. Clin. Immunol. 28, 635–639 (2008).

  41. 41

    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).

  42. 42

    Gondek, D. C., Lu, L. F., Quezada, S. A., Sakaguchi, S. & Noelle, R. J. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J. Immunol. 174, 1783–1786 (2005).

  43. 43

    Cao, X. et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 27, 635–646 (2007).

  44. 44

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

  45. 45

    Smigiel, K. S. et al. CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J. Exp. Med. 211, 121–136 (2014).

  46. 46

    Bergot, A.-S. et al. TCR sequences and tissue distribution discriminate the subsets of naïve and activated/memory Treg cells in mice. Eur. J. Immunol. 45, 1524–1534 (2015).

  47. 47

    Sugiyama, D. et al. Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl Acad. Sci. USA 110, 17945–17950 (2013).

  48. 48

    Koch, M. A. et al. T-Bet(+) Treg cells undergo abortive Th1 cell differentiation due to impaired expression of IL-12 receptor β2. Immunity 37, 501–510 (2012).

  49. 49

    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).

  50. 50

    Chaudhry, A. et al. CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326, 986–991 (2009). This is one of the first studies to introduce the concept that T reg cells express the same transcription factors as the cells they are supposed to suppress.

  51. 51

    Linterman, M. A. et al. Foxp3+ follicular regulatory T cells control the germinal center response. Nat. Med. 17, 975–982 (2011).

  52. 52

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

  53. 53

    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).

  54. 54

    Smigiel, K. S., Srivastava, S., Stolley, J. M. & Campbell, D. J. Regulatory T cell homeostasis: steady-state maintenance and modulation during inflammation. Immunol. Rev. 259, 40–59 (2014).

  55. 55

    Cheng, G. et al. IL-2 receptor signaling is essential for the development of Klrg1+ terminally differentiated T regulatory cells. J. Immunol. 189, 1780–1791 (2012).

  56. 56

    Pierson, W. et al. Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3(+) regulatory T cells. Nat. Immunol. 14, 959–965 (2013).

  57. 57

    Yu, A., Zhu, L., Altman, N. H. & Malek, T. R. A low interleukin-2 receptor signaling threshold supports the development and homeostasis of T regulatory cells. Immunity 30, 204–217 (2009).

  58. 58

    Castro, I., Yu, A., Dee, M. J. & Malek, T. R. The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J. Immunol. 187, 5170–5182 (2011).

  59. 59

    Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and disease. Cell 168, 960–976 (2017).

  60. 60

    Perl, A. Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases. Nat. Rev. Rheumatol. 12, 169–182 (2016).

  61. 61

    Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).

  62. 62

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

  63. 63

    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).

  64. 64

    Coe, D. J., Kishore, M. & Marelli-Berg, F. Metabolic regulation of regulatory T cell development and function. Front. Immunol. 5, 590 (2014).

  65. 65

    Powell, J. D., Pollizzi, K. N., Heikamp, E. B. & Horton, M. R. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30, 39–68 (2012).

  66. 66

    Walsh, P. T. et al. PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J. Clin. Invest. 116, 2521–2531 (2006).

  67. 67

    Delgoffe, G. M. et al. Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501, 252–256 (2013). This paper shows that the immune cell-expressed ligand SEMA4A and the T reg cell-expressed receptor NRP1 interact to potentiate T reg cell function and survival.

  68. 68

    Apostolidis, S. A. et al. Phosphatase PP2A is requisite for the function of regulatory T cells. Nat. Immunol. 17, 556–564 (2016). This paper shows that PP2A, a serine/threonine phosphatase, is important for the proper function of T reg cells and that its absence leads to extensive autoimmunity and multiple organ inflammation.

  69. 69

    Torgerson, T. R. & Ochs, H. D. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J. Allergy Clin. Immunol. 120, 744–750 (2007).

  70. 70

    Malek, T. R. & Bayer, A. L. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4, 665–674 (2004).

  71. 71

    Malek, T. R. The biology of interleukin-2. Annu. Rev. Immunol. 26, 453–479 (2008).

  72. 72

    Bernasconi, A. et al. Characterization of immunodeficiency in a patient with growth hormone insensitivity secondary to a novel STAT5b gene mutation. Pediatrics 118, e1584–e1592 (2006).

  73. 73

    Nadeau, K., Hwa, V. & Rosenfeld, R. G. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J. Pediatr. 158, 701–708 (2011).

  74. 74

    Schubert, D. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410–1416 (2014).

  75. 75

    Charbonnier, L. M. et al. Regulatory T cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol. 135, 217–227 (2015).

  76. 76

    Ohl, K. & Tenbrock, K. Regulatory T cells in systemic lupus erythematosus. Eur. J. Immunol. 45, 344–355 (2015).

  77. 77

    Lyssuk, E. Y., Torgashina, A. V., Soloviev, S. K., Nassonov, E. L. & Bykovskaia, S. N. Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus. Adv. Exp. Med. Biol. 601, 113–119 (2007).

  78. 78

    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).

  79. 79

    Venigalla, R. K. C. et al. Reduced CD4+,CD25- T cell sensitivity to the suppressive function of CD4+,CD25high, CD127−/low regulatory T cells in patients with active systemic lupus erythematosus. Arthritis Rheum. 58, 2120–2130 (2008).

  80. 80

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

  81. 81

    Comte, D. et al. Brief report: CD4+ T cells from patients with systemic lupus erythematosus respond poorly to exogenous interleukin-2. Arthritis Rheumatol. 69, 808–813 (2017).

  82. 82

    Afeltra, A. et al. The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study. Intern. Emerg. Med. 10, 677–683 (2015).

  83. 83

    Marwaha, A. K. et al. Cutting edge: increased IL-17-secreting T cells in children with new-onset type 1 diabetes. J. Immunol. 185, 3814–3818 (2010).

  84. 84

    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).

  85. 85

    Schneider, A. et al. The effector T cells of diabetic subjects are resistant to regulation via CD4+ FOXP3+ regulatory T cells. J. Immunol. 181, 7350–7355 (2008).

  86. 86

    Harden, J. L., Krueger, J. G. & Bowcock, A. M. The immunogenetics of psoriasis: a comprehensive review. J. Autoimmun. 64, 66–73 (2015).

  87. 87

    Soler, D. C. et al. Psoriasis patients exhibit impairment of the high potency CCR5(+) T regulatory cell subset. Clin. Immunol. 149, 111–118 (2013).

  88. 88

    Sugiyama, H. et al. Dysfunctional blood and target tissue CD4+CD25high regulatory T cells in psoriasis: mechanism underlying unrestrained pathogenic effector T cell proliferation. J. Immunol. 174, 164–173 (2005).

  89. 89

    Zhang, K. et al. Functional characterization of CD4+CD25+ regulatory T cells differentiated in vitro from bone marrow-derived haematopoietic cells of psoriasis patients with a family history of the disorder. Br. J. Dermatol. 158, 298–305 (2008).

  90. 90

    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).

  91. 91

    Balandina, A., Lecart, 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).

  92. 92

    Thiruppathi, M. et al. Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/-) T cells in patients with myasthenia gravis. Clin. Immunol. 145, 209–223 (2012).

  93. 93

    Alahgholi-Hajibehzad, M. et al. Regulatory function of CD4+CD25++ T cells in patients with myasthenia gravis is associated with phenotypic changes and STAT5 signaling: 1,25-Dihydroxyvitamin D3 modulates the suppressor activity. J. Neuroimmunol. 281, 51–60 (2015).

  94. 94

    Renton, A. E. et al. A genome-wide association study of myasthenia gravis. JAMA Neurol. 72, 396–404 (2015).

  95. 95

    Masuda, M. et al. Clinical implication of peripheral CD4+CD25+ regulatory T cells and Th17 cells in myasthenia gravis patients. J. Neuroimmunol. 225, 123–131 (2010).

  96. 96

    Makita, S. et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J. Immunol. 173, 3119–3130 (2004).

  97. 97

    Maul, J. et al. Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease. Gastroenterology 128, 1868–1878 (2005).

  98. 98

    Uhlig, H. H. et al. Characterization of Foxp3+CD4+CD25+ and IL-10-secreting CD4+CD25+ T cells during cure of colitis. J. Immunol. 177, 5852–5860 (2006).

  99. 99

    Monteleone, G. et al. Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J. Clin. Invest. 108, 601–609 (2001).

  100. 100

    Geremia, A., Biancheri, P., Allan, P., Corazza, G. R. & Di Sabatino, A. Innate and adaptive immunity in inflammatory bowel disease. Autoimmun. Rev. 13, 3–10 (2014).

  101. 101

    Agus, A., Planchais, J. & Sokol, H. Gut microbiota regulation of tryptophan metabolism in health and disease. Cell Host Microbe 23, 716–724 (2018).

  102. 102

    McFarland, H. F. & Martin, R. Multiple sclerosis: a complicated picture of autoimmunity. Nat. Immunol. 8, 913–919 (2007).

  103. 103

    Liu, Y., Teige, I., Birnir, B. & Issazadeh-Navikas, S. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12, 518–525 (2006).

  104. 104

    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).

  105. 105

    Noori-Zadeh, A. et al. Regulatory T cell number in multiple sclerosis patients: a meta-analysis. Mult. Scler. Relat. Disord. 5, 73–76 (2016).

  106. 106

    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).

  107. 107

    Lechler, R. I., Garden, O. A. & Turka, L. A. The complementary roles of deletion and regulation in transplantation tolerance. Nat. Rev. Immunol. 3, 147–158 (2003).

  108. 108

    Wood, K. J. & Sakaguchi, S. Regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 3, 199–210 (2003).

  109. 109

    Jiang, S., Herrera, O. & Lechler, R. I. New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. Curr. Opin. Immunol. 16, 550–557 (2004).

  110. 110

    Lee, K., Nguyen, V., Lee, K. M., Kang, S. M. & Tang, Q. Attenuation of donor-reactive T cells allows effective control of allograft rejection using regulatory T cell therapy. Am. J. Transplant. 14, 27–38 (2014).

  111. 111

    Koga, T. et al. CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance. J. Clin. Invest. 124, 2234–2245 (2014).

  112. 112

    Koga, T., Ichinose, K., Mizui, M., Crispin, J. C. & Tsokos, G. C. Calcium/calmodulin-dependent protein kinase IV suppresses IL-2 production and regulatory T cell activity in lupus. J. Immunol. 189, 3490–3496 (2012).

  113. 113

    Budhu, S. et al. Blockade of surface-bound TGF-beta on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci. Signal. 10, eaak9702 (2017).

  114. 114

    Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 475, 226–230 (2011). This study shows that tumour hypoxia promotes the recruitment of T reg cells through the induction of expression of the chemokine CCL28, which, in turn, promotes tumour tolerance and angiogenesis.

  115. 115

    Facciabene, A., Motz, G. T. & Coukos, G. T-Regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res. 72, 2162–2171 (2012).

  116. 116

    van der Stegen, S. J. C., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

  117. 117

    Whiteside, T. L. The role of regulatory T cells in cancer immunology. Immunotargets Ther. 4, 159–171 (2015).

  118. 118

    Halvorsen, E. C., Mahmoud, S. M. & Bennewith, K. L. Emerging roles of regulatory T cells in tumour progression and metastasis. Cancer Metastasis Rev. 33, 1025–1041 (2014).

  119. 119

    Valzasina, B., Piconese, S., Guiducci, C. & Colombo, M. P. Tumor-induced expansion of regulatory T cells by conversion of CD4+CD25- lymphocytes is thymus and proliferation independent. Cancer Res. 66, 4488–4495 (2006).

  120. 120

    Curti, A. et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood 109, 2871–2877 (2007).

  121. 121

    Zhou, G. & Levitsky, H. I. Natural regulatory T cells and de novo-induced regulatory T cells contribute independently to tumor-specific tolerance. J. Immunol. 178, 2155–2162 (2007).

  122. 122

    Hindley, J. P. et al. Analysis of the T cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors. Cancer Res. 71, 736–746 (2011).

  123. 123

    Plitas, G. et al. Regulatory T cells exhibit distinct features in human breast cancer. Immunity 45, 1122–1134 (2016).

  124. 124

    Malchow, S. et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science 339, 1219–1224 (2013).

  125. 125

    Darrasse-Jeze, G. et al. Tumor emergence is sensed by self-specific CD44hi memory Tregs that create a dominant tolerogenic environment for tumors in mice. J. Clin. Invest. 119, 2648–2662 (2009).

  126. 126

    Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 25, 1282–1293 (2017). This study presents the metabolic cascades that characterize T reg cells.

  127. 127

    Wang, H., Franco, F. & Ho, P. C. Metabolic regulation of Tregs in cancer: opportunities for immunotherapy. Trends Cancer 3, 583–592 (2017).

  128. 128

    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).

  129. 129

    Naganuma, M. et al. Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J. Immunol. 177, 2765–2769 (2006).

  130. 130

    Facciabene, A., Santoro, S. & Coukos, G. Know thy enemy: why are tumor-infiltrating regulatory T cells so deleterious? Oncoimmunology 1, 575–577 (2012).

  131. 131

    Shang, B., Liu, Y., Jiang, S. J. & Liu, Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci. Rep. 5, 15179 (2015).

  132. 132

    Bates, G. J. et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J. Clin. Oncol. 24, 5373–5380 (2006).

  133. 133

    Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).

  134. 134

    Ward-Hartstonge, K. A. & Kemp, R. A. Regulatory T cell heterogeneity and the cancer immune response. Clin. Transl Immunol. 6, e154 (2017).

  135. 135

    Saito, T. et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat. Med. 22, 679–684 (2016). This study shows that the presence of FOXP3low T cells in colorectal cancer tissues indicates a significantly better prognosis than the presence of predominantly FOXP3high T reg cells. This study has brought attention to the subpopulation of T reg cells with low FOXP3 expression, which should not be deleted when applying immunotherapeutic regimens.

  136. 136

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

  137. 137

    Trzonkowski, P. et al. Hurdles in therapy with regulatory T cells. Sci. Transl Med. 7, 304ps18 (2015).

  138. 138

    Taylor, P. A., Lees, C. J. & Blazar, B. R. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002).

  139. 139

    Cohen, J. L., Trenado, A., Vasey, D., Klatzmann, D. & Salomon, B. L. CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J. Exp. Med. 196, 401–406 (2002).

  140. 140

    Trzonkowski, P. et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127-T regulatory cells. Clin. Immunol. 133, 22–26 (2009).

  141. 141

    Di Ianni, M. et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117, 3921–3928 (2011).

  142. 142

    Brunstein, C. G. et al. Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117, 1061–1070 (2011).

  143. 143

    Juvet, S. C., Whatcott, A. G., Bushell, A. R. & Wood, K. J. Harnessing regulatory T cells for clinical use in transplantation: the end of the beginning. Am. J. Transplant. 14, 750–763 (2014).

  144. 144

    Stiller, C. et al. Cyclosporine for treatment of early type I diabetes: preliminary results. N. Engl. J. Med. 308, 1226–1227 (1983).

  145. 145

    Bougneres, P. et al. Factors associated with early remission of type I diabetes in children treated with cyclosporine. N. Engl. J. Med. 318, 663–670 (1988).

  146. 146

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

  147. 147

    Marek-Trzonkowska, N. et al. Therapy of type 1 diabetes with CD4(+)CD25(high)CD127-regulatory T cells prolongs survival of pancreatic islets - results of one year follow-up. Clin. Immunol. 153, 23–30 (2014).

  148. 148

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

  149. 149

    Kim, H. P. & Leonard, W. J. CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation. J. Exp. Med. 204, 1543–1551 (2007).

  150. 150

    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).

  151. 151

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

  152. 152

    Yang, R. et al. Hydrogen sulfide promotes Tet1- and Tet2-mediated Foxp3 demethylation to drive regulatory T Cell differentiation and maintain immune homeostasis. Immunity 43, 251–263 (2015).

  153. 153

    Gerriets, V. A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459–1466 (2016).

  154. 154

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

  155. 155

    Strauss, L., Czystowska, M., Szajnik, M., Mandapathil, M. & Whiteside, T. L. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLOS ONE 4, e5994 (2009).

  156. 156

    Fernandez, D. R. et al. Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation. J. Immunol. 182, 2063–2073 (2009).

  157. 157

    Kato, H. & Perl, A. Mechanistic target of rapamycin complex 1 expands Th17 and IL-4+ CD4-CD8- double-negative T cells and contracts regulatory T cells in systemic lupus erythematosus. J. Immunol. 192, 4134–4144 (2014).

  158. 158

    Warner, L. M., Adams, L. M. & Sehgal, S. N. Rapamycin prolongs survival and arrests pathophysiologic changes in murine systemic lupus erythematosus. Arthritis Rheum. 37, 289–297 (1994).

  159. 159

    Fernandez, D., Bonilla, E., Mirza, N., Niland, B. & Perl, A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2983–2988 (2006).

  160. 160

    Oaks, Z. et al. Mitochondrial dysfunction in the liver and antiphospholipid antibody production precede disease onset and respond to rapamycin in lupus-prone mice. Arthritis Rheumatol. 68, 2728–2739 (2016).

  161. 161

    Canaud, G. et al. Inhibition of the mTORC pathway in the antiphospholipid syndrome. N. Engl. J. Med. 371, 303–312 (2014).

  162. 162

    Lai, Z. W. et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391, 1186–1196 (2018).

  163. 163

    Tkachev, V. et al. Combined OX40L and mTOR blockade controls effector T cell activation while preserving Treg reconstitution after transplant. Sci. Transl Med. 9, eaan3085 (2017).

  164. 164

    Taylor, P. A. et al. Insights into the mechanism of FTY720 and compatibility with regulatory T cells for the inhibition of graft-versus-host disease (GVHD). Blood 110, 3480–3488 (2007).

  165. 165

    Chen, Y. B. et al. Increased Foxp3(+)Helios(+) regulatory T cells and decreased acute graft-versus-host disease after allogeneic bone marrow transplantation in patients receiving sirolimus and RGI-2001, an activator of invariant natural killer T cells. Biol. Blood Marrow Transplant. 23, 625–634 (2017).

  166. 166

    Link, W. et al. Chemical interrogation of FOXO3a nuclear translocation identifies potent and selective inhibitors of phosphoinositide 3-kinases. J. Biol. Chem. 284, 28392–28400 (2009).

  167. 167

    Liu, G. et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat. Immunol. 10, 769–777 (2009).

  168. 168

    Liu, G., Yang, K., Burns, S., Shrestha, S. & Chi, H. The S1P1-mTOR axis directs the reciprocal differentiation of TH1 and Treg cells. Nat. Immunol. 11, 1047–1056 (2010).

  169. 169

    Lai, Z. W. et al. N-Acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937–2946 (2012).

  170. 170

    Yin, Y. et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci. Transl Med. 7, 274ra18 (2015). This is one of the first studies to suggest that autoimmunity can be controlled through metabolism.

  171. 171

    Hancock, W. W., Akimova, T., Beier, U. H., Liu, Y. & Wang, L. HDAC inhibitor therapy in autoimmunity and transplantation. Ann. Rheum. Dis. 71 (Suppl. 2), i46–i54 (2012).

  172. 172

    Regna, N. L. et al. Specific HDAC6 inhibition by ACY-738 reduces SLE pathogenesis in NZB/W mice. Clin. Immunol. 162, 58–73 (2016).

  173. 173

    Zhang, Y. et al. Mice lacking histone deacetylase 6 have hyperacetylated tubulin but are viable and develop normally. Mol. Cell. Biol. 28, 1688–1701 (2008).

  174. 174

    de Zoeten, E. F. et al. Histone deacetylase 6 and heat shock protein 90 control the functions of Foxp3(+) T-regulatory cells. Mol. Cell. Biol. 31, 2066–2078 (2011).

  175. 175

    Fisson, S. et al. Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J. Exp. Med. 198, 737–746 (2003).

  176. 176

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

  177. 177

    Sadelain, M. CD19 CAR T cells. Cell 171, 1471 (2017).

  178. 178

    Blat, D., Zigmond, E., Alteber, Z., Waks, T. & Eshhar, Z. Suppression of murine colitis and its associated cancer by carcinoembryonic antigen-specific regulatory T cells. Mol. Ther. 22, 1018–1028 (2014).

  179. 179

    MacDonald, K. G. et al. Alloantigen-specific regulatory T cells generated with a chimeric antigen receptor. J. Clin. Invest. 126, 1413–1424 (2016).

  180. 180

    Boardman, D. A. et al. Expression of a chimeric antigen receptor specific for donor HLA class i enhances the potency of human regulatory T cells in preventing human skin transplant rejection. Am. J. Transplant. 17, 931–943 (2017).

  181. 181

    Adair, P. R., Kim, Y. C., Zhang, A.-H., Yoon, J. & Scott, D. W. Human Tregs made antigen specific by gene modification: the power to treat autoimmunity and antidrug antibodies with precision. Front. Immunol. 8, 1117 (2017).

  182. 182

    Rosenberg, S. A. et al. A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N. Engl. J. Med. 316, 889–897 (1987).

  183. 183

    Yu, A. et al. Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms support the use of low-dose IL-2 therapy in type-1 diabetes. Diabetes 64, 2172–2183 (2015).

  184. 184

    Laurence, A. et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26, 371–381 (2007).

  185. 185

    Ballesteros-Tato, A. et al. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36, 847–856 (2012).

  186. 186

    Gutierrez-Ramos, J. C., Andreu, J. L., Revilla, Y., Vinuela, E. & Martinez, C. Recovery from autoimmunity of MRL/lpr mice after infection with an interleukin-2/vaccinia recombinant virus. Nature 346, 271–274 (1990).

  187. 187

    Mizui, M. et al. IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J. Immunol. 193, 2168–2177 (2014).

  188. 188

    Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

  189. 189

    Suzuki, H. et al. Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268, 1472–1476 (1995).

  190. 190

    Willerford, D. M. et al. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3, 521–530 (1995).

  191. 191

    Malek, T. R., Yu, A., Vincek, V., Scibelli, P. & Kong, L. CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rβ-deficient mice: implications for the nonredundant function of IL-2. Immunity 17, 167–178 (2002).

  192. 192

    Lemoine, F. M. et al. Massive expansion of regulatory T cells following interleukin 2 treatment during a phase I-II dendritic cell-based immunotherapy of metastatic renal cancer. Int. J. Oncol. 35, 569–581 (2009).

  193. 193

    Rosenberg, S. A. IL-2: the first effective immunotherapy for human cancer. J. Immunol. 192, 5451–5458 (2014).

  194. 194

    Saadoun, D. et al. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 111, 5334–5341 (2008).

  195. 195

    Landau, D.-A. et al. Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum. 58, 2897–2907 (2008).

  196. 196

    Koreth, J. et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N. Engl. J. Med. 365, 2055–2066 (2011). This is the first study to show that low-dose IL-2 has clinical benefit in patients with GVHD linked to the expansion of T reg cells.

  197. 197

    Kennedy-Nasser, A. A. et al. Ultra low-dose IL-2 for GVHD prophylaxis after allogeneic hematopoietic stem cell transplantation mediates expansion of regulatory T cells without diminishing antiviral and antileukemic activity. Clin. Cancer Res. 20, 2215–2225 (2014).

  198. 198

    Castela, E. et al. Effects of low-dose recombinant interleukin 2 to promote T-regulatory cells in alopecia areata. JAMA Dermatol. 150, 748–751 (2014).

  199. 199

    Humrich, J. Y. et al. A3.11 Induction of remission by low-dose IL-2-therapy in one SLE patient with increased disease activity refractory to standard therapies: a case report. Ann. Rheum. Dis. 73, A46 (2014).

  200. 200

    von Spee-Mayer, C. et al. Low-dose interleukin-2 selectively corrects regulatory T cell defects in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 75, 1407–1415 (2015).

  201. 201

    He, J. et al. Low-dose interleukin-2 treatment selectively modulates CD4(+) T cell subsets in patients with systemic lupus erythematosus. Nat. Med. 22, 991–993 (2016).

  202. 202

    Moulton, V. R. et al. Pathogenesis of human systemic lupus erythematosus: a cellular perspective. Trends Mol. Med. 23, 615–635 (2017).

  203. 203

    Hartemann, A. et al. Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 1, 295–305 (2013).

  204. 204

    Mitra, S. et al. Interleukin-2 activity can be fine tuned with engineered receptor signaling clamps. Immunity 42, 826–838 (2015).

  205. 205

    Goodson, R. J. & Katre, N. V. Site-directed pegylation of recombinant interleukin-2 at its glycosylation site. Biotechnology 8, 343–346 (1990).

  206. 206

    Bell, C. J. M. et al. Sustained in vivo signaling by long-lived IL-2 induces prolonged increases of regulatory T cells. J. Autoimmun. 56, 66–80 (2015).

  207. 207

    Yeh, P. et al. Design of yeast-secreted albumin derivatives for human therapy: biological and antiviral properties of a serum albumin-CD4 genetic conjugate. Proc. Natl Acad. Sci. USA 89, 1904–1908 (1992).

  208. 208

    Yao, Z., Dai, W., Perry, J., Brechbiel, M. W. & Sung, C. Effect of albumin fusion on the biodistribution of interleukin-2. Cancer Immunol. Immunother. 53, 404–410 (2004).

  209. 209

    Boyman, O., Kovar, M., Rubinstein, M. P., Surh, C. D. & Sprent, J. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311, 1924–1927 (2006).

  210. 210

    Arenas-Ramirez, N. et al. Improved cancer immunotherapy by a CD25-mimobody conferring selectivity to human interleukin-2. Sci. Transl Med. 8, 367ra166 (2016).

  211. 211

    Trotta, E. et al. A human anti-IL-2 antibody that potentiates regulatory T cells by a structure-based mechanism. Nat. Med. 24, 1005–1014 (2018). This study shows that a fully human anti-IL-2 antibody stabilizes IL-2 in a conformation that results in the preferential STAT5 phosphorylation of T reg cells in vitro and their selective expansion in vivo to mitigate experimental diabetes and multiple sclerosis.

  212. 212

    Mahnke, K. et al. The dendritic cell receptor for endocytosis, DEC-205, can recycle and enhance antigen presentation via major histocompatibility complex class II-positive lysosomal compartments. J. Cell Biol. 151, 673–684 (2000).

  213. 213

    Polansky, J. K. et al. DNA methylation controls Foxp3 gene expression. Eur. J. Immunol. 38, 1654–1663 (2008).

  214. 214

    Bruder, D. et al. On the edge of autoimmunity: T cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. Diabetes 54, 3395–3401 (2005).

  215. 215

    Hawiger, D., Masilamani, R. F., Bettelli, E., Kuchroo, V. K. & Nussenzweig, M. C. Immunological unresponsiveness characterized by increased expression of CD5 on peripheral T cells induced by dendritic cells in vivo. Immunity 20, 695–705 (2004).

  216. 216

    Raker, V. K., Domogalla, M. P. & Steinbrink, K. Tolerogenic dendritic cells for regulatory T cell induction in man. Front. Immunol. 6, 569 (2015).

  217. 217

    Benham, H. et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci. Transl Med. 7, 290ra87 (2015).

  218. 218

    Johnson, K. P. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. 1995. Neurology 57, S16–S24 (2001).

  219. 219

    Jee, Y. et al. CD4(+)CD25(+) regulatory T cells contribute to the therapeutic effects of glatiramer acetate in experimental autoimmune encephalomyelitis. Clin. Immunol. 125, 34–42 (2007).

  220. 220

    Sharabi, A., Zinger, H., Zborowsky, M., Sthoeger, Z. M. & Mozes, E. A peptide based on the complementarity-determining region 1 of an autoantibody ameliorates lupus by up-regulating CD4+CD25+ cells and TGF-beta. Proc. Natl Acad. Sci. USA 103, 8810–8815 (2006).

  221. 221

    Sthoeger, Z. M. et al. Treatment of lupus patients with a tolerogenic peptide, hCDR1 (Edratide): immunomodulation of gene expression. J. Autoimmun 33, 77–82 (2009).

  222. 222

    Sharabi, A., Lapter, S. & Mozes, E. Bcl-xL is required for the development of functional regulatory CD4 cells in lupus-afflicted mice following treatment with a tolerogenic peptide. J. Autoimmun. 34, 87–95 (2010).

  223. 223

    Sharabi, A. & Mozes, E. The suppression of murine lupus by a tolerogenic peptide involves foxp3-expressing CD8 cells that are required for the optimal induction and function of foxp3-expressing CD4 cells. J. Immunol. 181, 3243–3251 (2008).

  224. 224

    Urowitz, M. B., Isenberg, D. A. & Wallace, D. J. Safety and efficacy of hCDR1 (Edratide) in patients with active systemic lupus erythematosus: results of phase II study. Lupus Sci. Med. 2, e000104 (2015).

  225. 225

    Kang, H. K., Michaels, M. A., Berner, B. R. & Datta, S. K. Very low-dose tolerance with nucleosomal peptides controls lupus and induces potent regulatory T cell subsets. J. Immunol. 174, 3247–3255 (2005).

  226. 226

    Hahn, B. H., Singh, R. P., La Cava, A. & Ebling, F. M. Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J. Immunol. 175, 7728–7737 (2005).

  227. 227

    Leavenworth, J. W., Wang, X., Wenander, C. S., Spee, P. & Cantor, H. Mobilization of natural killer cells inhibits development of collagen-induced arthritis. Proc. Natl Acad. Sci. USA 108, 14584–14589 (2011).

  228. 228

    Gertel, S., Serre, G., Shoenfeld, Y. & Amital, H. Immune tolerance induction with multiepitope peptide derived from citrullinated autoantigens attenuates arthritis manifestations in adjuvant arthritis rats. J. Immunol. 194, 5674–5680 (2015).

  229. 229

    Deshmukh, U. S., Bagavant, H., Lewis, J., Gaskin, F. & Fu, S. M. Epitope spreading within lupus-associated ribonucleoprotein antigens. Clin. Immunol. 117, 112–120 (2005).

  230. 230

    Herrath, J. et al. The inflammatory milieu in the rheumatic joint reduces regulatory T cell function. Eur. J. Immunol. 41, 2279–2290 (2011).

  231. 231

    Vargas-Rojas, M. I., Crispin, J. C., Richaud-Patin, Y. & Alcocer-Varela, J. Quantitative and qualitative normal regulatory T cells are not capable of inducing suppression in SLE patients due to T cell resistance. Lupus 17, 289–294 (2008).

  232. 232

    Ghiringhelli, F. et al. Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients. Cancer Immunol. Immunother. 56, 641–648 (2007).

  233. 233

    Lutsiak, M. E. et al. Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide. Blood 105, 2862–2868 (2005).

  234. 234

    Ge, Y. et al. Metronomic cyclophosphamide treatment in metastasized breast cancer patients: immunological effects and clinical outcome. Cancer Immunol. Immunother. 61, 353–362 (2012).

  235. 235

    Adotevi, O. et al. A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J. Immunother. 33, 991–998 (2010).

  236. 236

    Desar, I. M. et al. Sorafenib reduces the percentage of tumour infiltrating regulatory T cells in renal cell carcinoma patients. Int. J. Cancer 129, 507–512 (2011).

  237. 237

    Coussens, L. M. & Werb, Z. Inflammation and cancer. Nature 420, 860–867 (2002).

  238. 238

    Curiel, T. J. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 10, 942–949 (2004).

  239. 239

    Chang, D. K. et al. Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology 5, e1090075 (2016).

  240. 240

    Ogura, M. et al. Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T cell lymphoma and cutaneous T cell lymphoma. J. Clin. Oncol. 32, 1157–1163 (2014).

  241. 241

    Ishida, T. et al. Mogamulizumab for relapsed adult T cell leukemia-lymphoma: updated follow-up analysis of phase I and II studies. Cancer Sci. 108, 2022–2029 (2017).

  242. 242

    Ifuku, H. et al. Fatal reactivation of hepatitis B virus infection in a patient with adult T cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab. Hepatol. Res. 45, 1363–1367 (2015).

  243. 243

    Kurose, K. et al. Phase Ia study of FoxP3+ CD4 Treg depletion by infusion of a humanized anti-CCR4 antibody, KW-0761, in cancer patients. Clin. Cancer Res. 21, 4327–4336 (2015).

  244. 244

    De Simone, M. et al. Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells. Immunity 45, 1135–1147 (2016).

  245. 245

    Attia, P. et al. Selective elimination of human regulatory T lymphocytes in vitro with the recombinant immuno-toxin LMB-2. J. Immunother. 29, 208–214 (2006).

  246. 246

    Rech, A. J. et al. CD25 blockade depletes and selectively reprograms regulatory T cells in concert with immunotherapy in cancer patients. Sci. Transl Med. 4, 134ra62 (2012).

  247. 247

    Kreitman, R. J. et al. Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies. J. Clin. Oncol. 18, 1622–1636 (2000).

  248. 248

    Kreitman, R. J. et al. Complete remissions of adult T cell leukemia with anti-CD25 recombinant immunotoxin LMB-2 and chemotherapy to block immunogenicity. Clin. Cancer Res. 22, 310–318 (2016).

  249. 249

    Powell, D. J. Jr. et al. Administration of a CD25-directed immunotoxin, LMB-2, to patients with metastatic melanoma induces a selective partial reduction in regulatory T cells in vivo. J. Immunol. 179, 4919–4928 (2007).

  250. 250

    Dannull, J. et al. Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells. J. Clin. Invest. 115, 3623–3633 (2005).

  251. 251

    Attia, P., Maker, A. V., Haworth, L. R., Rogers-Freezer, L. & Rosenberg, S. A. Inability of a fusion protein of IL-2 and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes in patients with melanoma. J. Immunother. 28, 582–592 (2005).

  252. 252

    Maury, S. et al. Lymphodepletion followed by infusion of suicide gene-transduced donor lymphocytes to safely enhance their antitumor effect: a phase I/II study. Leukemia 28, 2406–2410 (2014).

  253. 253

    Attia, P. et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J. Clin. Oncol. 23, 6043–6053 (2005).

  254. 254

    Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711–723 (2010).

  255. 255

    Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).

  256. 256

    Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695–1710 (2013).

  257. 257

    Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. & Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717–1725 (2009).

  258. 258

    Paterson, A. M. et al. Deletion of CTLA-4 on regulatory T cells during adulthood leads to resistance to autoimmunity. J. Exp. Med. 212, 1603–1621 (2015).

  259. 259

    Phan, G. Q. et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc. Natl Acad. Sci. USA 100, 8372–8377 (2003).

  260. 260

    Hodi, F. S. et al. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 17, 1558–1568 (2016).

  261. 261

    Zhao, H., Liao, X. & Kang, Y. Tregs: where we are and what comes next? Front. Immunol. 8, 1578 (2017).

  262. 262

    Sasidharan Nair, V. & Elkord, E. Immune checkpoint inhibitors in cancer therapy: a focus on T-regulatory cells. Immunol. Cell Biol. 96, 21–33 (2018).

  263. 263

    Sabatos, C. A. et al. Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance. Nat. Immunol. 4, 1102–1110 (2003).

  264. 264

    Coe, D. et al. Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy. Cancer Immunol. Immunother. 59, 1367–1377 (2010).

  265. 265

    Cohen, A. D. et al. Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation. PLOS ONE 5, e10436 (2010).

  266. 266

    Schaer, D. A., Murphy, J. T. & Wolchok, J. D. Modulation of GITR for cancer immunotherapy. Curr. Opin. Immunol. 24, 217–224 (2012).

  267. 267

    Schaer, D. A. et al. GITR pathway activation abrogates tumor immune suppression through loss of regulatory T cell lineage stability. Cancer Immunol. Res. 1, 320–331 (2013).

  268. 268

    Ko, K. et al. Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J. Exp. Med. 202, 885–891 (2005).

  269. 269

    Lu, L. et al. Combined PD-1 blockade and GITR triggering induce a potent antitumor immunity in murine cancer models and synergizes with chemotherapeutic drugs. J. Transl Med. 12, 36 (2014).

  270. 270

    Shimizu, J., Yamazaki, S., Takahashi, T., Ishida, Y. & Sakaguchi, S. Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat. Immunol. 3, 135–142 (2002).

  271. 271

    Murphy, J. T. et al. Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal antibody in mice. Blood 123, 2172–2180 (2014).

  272. 272

    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).

  273. 273

    Ephrem, A. et al. Modulation of Treg cells/T effector function by GITR signaling is context-dependent. Eur. J. Immunol. 43, 2421–2429 (2013).

  274. 274

    Liao, G. et al. GITR engagement preferentially enhances proliferation of functionally competent CD4+CD25+FoxP3+ regulatory T cells. Int. Immunol. 22, 259–270 (2010).

  275. 275

    Curti, B. D. et al. OX40 is a potent immune-stimulating target in late-stage cancer patients. Cancer Res. 73, 7189–7198 (2013).

  276. 276

    Sturgill, E. R. & Redmond, W. L. TNFR agonists: a review of current biologics targeting OX40, 4-1BB, CD27, and GITR. Am. J. Hematol. Oncol. 13, 4–15 (2017).

  277. 277

    Lesokhin, A. M., Callahan, M. K., Postow, M. A. & Wolchok, J. D. On being less tolerant: enhanced cancer immunosurveillance enabled by targeting checkpoints and agonists of T cell activation. Sci. Transl Med. 7, 280sr1 (2015).

  278. 278

    Knee, D. A., Hewes, B. & Brogdon, J. L. Rationale for anti-GITR cancer immunotherapy. Eur. J. Cancer 67, 1–10 (2016).

  279. 279

    Torrey, H. et al. Targeting TNFR2 with antagonistic antibodies inhibits proliferation of ovarian cancer cells and tumor-associated Tregs. Sci. Signal. 10, eaaf8608 (2017).

  280. 280

    Faustman, D. & Davis, M. TNF receptor 2 pathway: drug target for autoimmune diseases. Nat. Rev. Drug Discov. 9, 482–493 (2010).

  281. 281

    He, X. et al. A TNFR2-agonist facilitates high purity expansion of human low purity Treg cells. PLOS ONE 11, e0156311 (2016).

  282. 282

    Okubo, Y., Mera, T., Wang, L. & Faustman, D. L. Homogeneous expansion of human T-regulatory cells via tumor necrosis factor receptor 2. Sci. Rep. 3, 3153 (2013).

  283. 283

    Chopra, M. et al. Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion. J. Exp. Med. 213, 1881–1900 (2016).

  284. 284

    Fallarino, F. et al. Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol. 4, 1206–1212 (2003).

  285. 285

    Fallarino, F. et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J. Immunol. 176, 6752–6761 (2006).

  286. 286

    Prendergast, G. C., Malachowski, W. P., DuHadaway, J. B. & Muller, A. J. Discovery of IDO1 inhibitors: from bench to bedside. Cancer Res. 77, 6795–6811 (2017).

  287. 287

    Vacchelli, E. et al. Trial watch: IDO inhibitors in cancer therapy. Oncoimmunology 3, e957994 (2014).

  288. 288

    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).

  289. 289

    Soares, K. C. et al. TGF-β blockade depletes T regulatory cells from metastatic pancreatic tumors in a vaccine dependent manner. Oncotarget 6, 43005–43015 (2015).

  290. 290

    Turnis, M. E. et al. Interleukin-35 limits anti-tumor immunity. Immunity 44, 316–329 (2016).

  291. 291

    Yu, P. et al. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J. Exp. Med. 201, 779–791 (2005).

  292. 292

    Lu, J. et al. Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol. Med. Rep. 12, 2668–2676 (2015).

  293. 293

    Overacre-Delgoffe, A. E. et al. Interferon-γ drives Treg fragility to promote anti-tumor immunity. Cell 169, 1130–1141 (2017). This paper shows that NRP1 is required to maintain intratumoural T reg stability and function and that NRP1-deficient T reg cells produce IFNγ, which promotes T reg cell fragility and boosts antitumour activity.

  294. 294

    Grinberg-Bleyer, Y. et al. IL-2 reverses established type 1 diabetes in NOD mice by a local effect on pancreatic regulatory T cells. J. Exp. Med. 207, 1871–1878 (2010).

  295. 295

    Clever, D. et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166, 1117–1131 (2016). This is a novel study that explains the abundance of lung metastases by various tumours. Low oxygen pressure promotes the development of T reg cells, which promote tumour growth.

  296. 296

    Chen, P. L. et al. Analysis of immune signatures in longitudinal tumor samples yields insight into biomarkers of response and mechanisms of resistance to immune checkpoint blockade. Cancer Discov. 6, 827–837 (2016).

  297. 297

    Linsley, P. S., Chaussabel, D. & Speake, C. The relationship of immune cell signatures to patient survival varies within and between tumor types. PLOS ONE 10, e0138726 (2015).

  298. 298

    Kitagawa, Y. et al. Guidance of regulatory T cell development by Satb1-dependent super-enhancer establishment. Nat. Immunol. 18, 173–183 (2017). This study introduces the concept that super-enhancers can be modulated to dictate cell lineage differentiation.

  299. 299

    Zhou, X., Tang, J., Cao, H., Fan, H. & Li, B. Tissue resident regulatory T cells: novel therapeutic targets for human disease. Cell. Mol. Immunol. 12, 543–552 (2015).

  300. 300

    Hovhannisyan, Z., Treatman, J., Littman, D. R. & Mayer, L. Characterization of interleukin-17-producing regulatory T cells in inflamed intestinal mucosa from patients with inflammatory bowel diseases. Gastroenterology 140, 957–965 (2011).

  301. 301

    Cipolletta, D. et al. PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549–553 (2012). This study shows that T reg cells that infiltrate tissues and become tissue-resident T cells express transcription factors that are master regulators of the specific tissue. PPARγ is a master regulator of adipose tissue.

  302. 302

    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).

  303. 303

    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).

  304. 304

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

  305. 305

    Malhotra, N. et al. RORα-expressing T regulatory cells restrain allergic skin inflammation. Sci. Immunol. 3, eaao6923 (2018). This study shows that expression of retinoid-related orphan receptor-α (RORα) in skin-resident T reg cells is important for restraining allergic skin inflammation.

  306. 306

    Pesenacker, A. M., Broady, R. & Levings, M. K. Control of tissue-localized immune responses by human regulatory T cells. Eur. J. Immunol. 45, 333–343 (2015).

  307. 307

    Akimova, T. et al. Human lung tumor FOXP3+ Tregs upregulate four “Treg-locking” transcription factors. JCI Insight 2, 94075 (2017).

  308. 308

    Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013). This study introduces the concept that T reg cells can participate in the repair of injured tissue through the factors they produce. T reg cells repair injured muscle through the production of amphiregulin.

  309. 309

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

  310. 310

    Zaiss, D. M. et al. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 38, 275–284 (2013).

  311. 311

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

  312. 312

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

  313. 313

    Ali, N. et al. Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169, 1119–1129 (2017). This study provides another example of T reg cells being involved in tissue repair and/or regeneration. Skin-resident T reg cells were found to express preferentially high levels of the NOTCH ligand family member jagged 1, which promoted the function of skin stem cells.

  314. 314

    Zacchigna, S. et al. Paracrine effect of regulatory T cells promotes cardiomyocyte proliferation during pregnancy and after myocardial infarction. Nat. Commun. 9, 2432 (2018).

  315. 315

    Bieber, A. J., Kerr, S. & Rodriguez, M. Efficient central nervous system remyelination requires T cells. Ann. Neurol. 53, 680–684 (2003).

  316. 316

    Dombrowski, Y. et al. Regulatory T cells promote myelin regeneration in the central nervous system. Nat. Neurosci. 20, 674–680 (2017).

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Acknowledgements

The authors' work was supported by US National Institutes of Health (NIH) grants AI42269, R37AI49954, AI068787, AI085567 and AR064350 (G.C.T.) and R21-CA195334, R01-AI131648 and the Sylvester Comprehensive Cancer Center at the University of Miami (T.R.M.).

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Correspondence to Amir Sharabi or David Klatzmann or George C. Tsokos.

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G.C.T. is a consultant for Johnson & Johnson and a science advisory board member for Abpro and Silicon Therapeutics (appointments that are not related to the work discussed herein). D.K. is an inventor on a patent application claiming low-dose IL-2 for therapy of autoimmune diseases, which is owned by his academic institution and licensed to ILTOO Pharma; D.K. advises for and holds shares in ILTOO Pharma. The University of Miami and T.R.M. have a patent pending (WO2016022671A1) on IL-2/CD25 fusion proteins that has been licensed exclusively to Bristol-Myers Squibb and have a collaboration and sponsored research & licensing agreement with Bristol-Myers Squibb. A.S., M.G.T. and Y.D. declare no competing interests.

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Glossary

Self-tolerance

The inability to respond to self-antigens.

CD4+ T cells

T cells that recognize peptides presented by major histocompatibility complex class II molecules and provide help to B cells to produce antibodies or to CD8+ cells to produce cytotoxic responses.

Effector T cells

(Teff cells). Short-lived activated cells that defend the body in an immune response.

T helper 1 cells

(TH1 cells). Cells that produce interleukin 2, interferon-γ and tumour necrosis factor and are pro-inflammatory.

T helper 17 cells

(TH17 cells). Cells that produce interleukin-17 and play an important role in maintaining mucosal barriers and contributing to pathogen clearance at mucosal surfaces; they also propagate autoimmune and inflammatory pathology.

Co-stimulatory molecule

A membrane-bound or secreted product that is required for co-stimulation. This second signal (in addition to T cell receptor engagement) from an antigen-presenting cell to a T cell allows the T cell to become activated and produce cytokines. CD28 (on T cells) is the best known example.

Antigen-presenting cells

(APCs). Cells that display antigen complexed with major histocompatibility complex molecules on their surfaces, which they present to T cells.

Dendritic cells

(DCs). Cells that are named for their surface projections (which resemble the dendrites of neurons). They continuously sample the environment for antigen, which they process and present to T cells.

CD8+ T cells

Cytotoxic T cells that recognize peptides presented by major histocompatibility complex class I molecules.

Natural killer (NK) cells

Cytotoxic lymphocytes critical to the innate immune system that provide rapid responses to viral infection and respond to tumour formation. They express an array of activating and inhibitory receptors and produce interferon-γ.

T helper 2 cells

(TH2 cells). They promote allergic responses and provide help to B cells. Cells that can also promote resolution of inflammation and produce interleukin 4 (IL-4), IL-5, IL-6 and IL-10.

T follicular helper cells

(TFH cells). Antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleens and Peyer's patches.

Antibody-dependent cell-mediated cytotoxicity

(ADCC). In this process, targeted cells become coated with antibody, and are then lysed by effector cells that have cytolytic activity and specific immunoglobulin crystallizable fragment (Fc) receptors. Lysis requires direct cell-to-cell contact and does not involve complement.

Complement-mediated cytotoxicity

A process that leads to the lysis of cells coated with immunoglobulin, a marker that is able to activate complement.

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Sharabi, A., Tsokos, M., Ding, Y. et al. Regulatory T cells in the treatment of disease. Nat Rev Drug Discov 17, 823–844 (2018). https://doi.org/10.1038/nrd.2018.148

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