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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  18. 18

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

    CAS  Article  Google Scholar 

  19. 19

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  70. 70

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  71. 71

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  94. 94

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

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  102. 102

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  123. 123

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  133. 133

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134

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

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137

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

    PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  144. 144

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  151. 151

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161

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

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  177. 177

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  184. 184

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  188. 188

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  189. 189

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  193. 193

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  194. 194

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  202. 202

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  204. 204

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  213. 213

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  237. 237

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  254. 254

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  255. 255

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  261. 261

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  266. 266

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  278. 278

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  280. 280

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  281. 281

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  284. 284

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

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  287. 287

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

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  Google Scholar 

  290. 290

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  307. 307

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

    PubMed  Article  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  309. 309

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  311. 311

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  312. 312

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  315. 315

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

    PubMed  Article  PubMed Central  Google Scholar 

  316. 316

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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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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Competing interests

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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