Regulatory T Cells: Broadening Applicability

  • Franziska Maria Uhl
  • Robert ZeiserEmail author
Part of the Advances and Controversies in Hematopoietic Transplantation and Cell Therapy book series (ACHTCT)


Since their discovery in 1995, regulatory T cells (Treg) have been established as an anti-inflammatory T cell population which attenuates and modulates immune responses on multiple levels including initiation, progression, and termination. Over the past decades intensive research on this new T cell subtype led to deeper understanding of the intrinsic mechanisms of the immune system to contain and control inflammatory reactions. Graft-versus-host disease (GvHD) developing after allogeneic hematopoietic cell transplantation (allo-HCT) belongs to a variety of diseases, in which the immune system runs amok and attacks the own body in an autoreactive manner. As soon as the immense potential of Treg to downregulate excessive autoimmune responses became evident, multiple translational approaches have been pursued in order to unravel the suppressive capability of Treg in GvHD and be able to control or even prevent this fatal complication in the clinical setting. Ultimately, researchers and clinicians want to find a way to establish long-lasting tolerance within the graft without diminishing the beneficial graft-versus-tumor/graft-versus-leukemia (GvT/GvL) effect.

The chapter will give an overview of Treg characterization and functional abilities in order to explain thereafter their diverse influence in the pathogenesis of GvHD which is mainly studied in preclinical models and conclude with a review over completed and current clinical trials.


Regulatory T cells Immunotherapy Hematopoietic cell transplant Graft-versus-host disease Graft-versus-tumor effect Graft-versus-leukemia effect Conventional T cells 


  1. Adotevi O et al (2010) A decrease of regulatory T cells correlates with overall survival after sunitinib-based antiangiogenic therapy in metastatic renal cancer patients. J Immunother 33:991–998PubMedCrossRefGoogle Scholar
  2. Anderson BE et al (2004) Recipient CD4+ T cells that survive irradiation regulate chronic graft-versus-host disease. Blood 104:1565–1573PubMedCrossRefGoogle Scholar
  3. Battaglia M, Stabilini A, Roncarolo MG (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748PubMedCrossRefGoogle Scholar
  4. Battaglia M et al (2006) Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 177:8338–8347PubMedCrossRefGoogle Scholar
  5. Battaglia M, Stabilini A, Tresoldi E (2012) Expanding human T regulatory cells with the mTOR-inhibitor rapamycin. Methods Mol Biol 821:279–293PubMedCrossRefGoogle Scholar
  6. Bauer CA et al (2014) Dynamic Treg interactions with intratumoral APCs promote local CTL dysfunction. J Clin Invest 124:2425–2440PubMedPubMedCentralCrossRefGoogle Scholar
  7. Bayer AL et al (2009) Host CD4+CD25+ T cells can expand and comprise a major component of the Treg compartment after experimental HCT. Blood 113:733–743PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bennett CL et al (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27:20–21PubMedCrossRefGoogle Scholar
  9. Bensinger SJ et al (2004) Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol 172:5287–5296PubMedPubMedCentralCrossRefGoogle Scholar
  10. Beres A, Komorowski R, Mihara M, Drobyski WR (2011) Instability of Foxp3 expression limits the ability of induced regulatory T cells to mitigate graft versus host disease. Clin Cancer Res 17:3969–3983PubMedPubMedCentralCrossRefGoogle Scholar
  11. Beres AJ et al (2012) CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity. J Immunol 189:464–474PubMedPubMedCentralCrossRefGoogle Scholar
  12. Bergerot I et al (1999) Insulin B-chain reactive CD4+ regulatory T-cells induced by oral insulin treatment protect from type 1 diabetes by blocking the cytokine secretion and pancreatic infiltration of diabetogenic effector T-cells. Diabetes 48:1720–1729PubMedCrossRefGoogle Scholar
  13. Bluestone JA, Abbas AK (2003) Natural versus adaptive regulatory T cells. Nat Rev Immunol 3:253–257PubMedCrossRefGoogle Scholar
  14. Boissonnas A et al (2010) Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 32:266–278PubMedCrossRefGoogle Scholar
  15. Booth NJ et al (2010) Different proliferative potential and migratory characteristics of human CD4+ regulatory T cells that express either CD45RA or CD45RO. J Immunol 184:4317–4326PubMedCrossRefGoogle Scholar
  16. Brunkow ME et al (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27:68–73PubMedCrossRefGoogle Scholar
  17. Brunstein CG, Miller JS, Cao Q, McKenna DH, Hippen KL, Curtsinger J et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117:1061–1070PubMedPubMedCentralCrossRefGoogle Scholar
  18. Brunstein CG, Miller JS, McKenna DH, Hippen KL, DeFor TE, Sumstad D et al (2016) Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile and clinical effect. Blood 127:1044–1051PubMedPubMedCentralCrossRefGoogle Scholar
  19. Camirand G et al (2014) CD45 ligation expands Tregs by promoting interactions with DCs. J Clin Invest 124:4603–4613PubMedPubMedCentralCrossRefGoogle Scholar
  20. Campbell DJ, Koch MA (2011) Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat Rev Immunol 11:119–130PubMedPubMedCentralCrossRefGoogle Scholar
  21. Caramalho I et al (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403–411PubMedPubMedCentralCrossRefGoogle Scholar
  22. Cederbom L, Hall H, Ivars F (2000) CD4+CD25+ regulatory T cells down-regulate co-stimulatory molecules on antigen-presenting cells. Eur J Immunol 30:1538–1543PubMedCrossRefGoogle Scholar
  23. Chaudhry A et al (2009) CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science 326:986–991PubMedPubMedCentralCrossRefGoogle Scholar
  24. Chen W et al (2003) 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 198:1875–1886PubMedPubMedCentralCrossRefGoogle Scholar
  25. Chen ML et al (2005) Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci U S A 102:419–424PubMedCrossRefPubMedCentralGoogle Scholar
  26. Chen X et al (2007) Absence of regulatory T-cell control of TH1 and TH17 cells is responsible for the autoimmune-mediated pathology in chronic graft-versus-host disease. Blood 110:3804–3813PubMedPubMedCentralCrossRefGoogle Scholar
  27. Chen X et al (2009) Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood 114:891–900PubMedPubMedCentralCrossRefGoogle Scholar
  28. Choi J et al (2010) In vivo administration of hypomethylating agents mitigate graft-versus-host disease without sacrificing graft-versus-leukemia. Blood 116:129–139PubMedPubMedCentralCrossRefGoogle Scholar
  29. Chung DJ et al (2009) Indoleamine 2,3-dioxygenase-expressing mature human monocyte-derived dendritic cells expand potent autologous regulatory T cells. Blood 114:555–563PubMedPubMedCentralCrossRefGoogle Scholar
  30. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL (2002) CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 196:401–406PubMedPubMedCentralCrossRefGoogle Scholar
  31. Collison LW et al (2007) The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 450:566–569PubMedCrossRefGoogle Scholar
  32. Collison LW, Pillai MR, Chaturvedi V, Vignali DA (2009) Regulatory T cell suppression is potentiated by target T cells in a cell contact, IL-35- and IL-10-dependent manner. J Immunol 182:6121–6128PubMedPubMedCentralCrossRefGoogle Scholar
  33. Collison LW et al (2010) IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 11:1093–1101PubMedPubMedCentralCrossRefGoogle Scholar
  34. Curiel TJ et al (2004) Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10:942–949PubMedCrossRefGoogle Scholar
  35. Deaglio S et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204:1257–1265PubMedPubMedCentralCrossRefGoogle Scholar
  36. Demirkiran A et al (2009) Conversion from calcineurin inhibitor to mycophenolate mofetil-based immunosuppression changes the frequency and phenotype of CD4+FOXP3+ regulatory T cells. Transplantation 87:1062–1068PubMedCrossRefGoogle Scholar
  37. Di Ianni M, Falzetti F, Carotti A, Terenzi A, Castellino F, Bonifacio E et al (2011) Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood 117:3921–3928PubMedCrossRefGoogle Scholar
  38. Duramad O, Laysang A, Li J, Ishii Y, Namikawa R (2011) Pharmacologic expansion of donor-derived, naturally occurring CD4(+)Foxp3(+) regulatory T cells reduces acute graft-versus-host disease lethality without abrogating the graft-versus-leukemia effect in murine models. Biol Blood Marrow Transplant 17:1154–1168PubMedCrossRefGoogle Scholar
  39. Durham NM et al (2014) Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080PubMedPubMedCentralCrossRefGoogle Scholar
  40. Earle KE et al (2005) In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clin Immunol 115:3–9PubMedCrossRefGoogle Scholar
  41. Edinger M et al (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9:1144–1150PubMedCrossRefGoogle Scholar
  42. Ermann J et al (2005) Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105:2220–2226PubMedCrossRefGoogle Scholar
  43. Fallarino F et al (2003) Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 4:1206–1212PubMedCrossRefGoogle Scholar
  44. Fantini MC et al (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153PubMedCrossRefGoogle Scholar
  45. Ferrara JL, Levine JE, Reddy P, Holler E (2009) Graft-versus-host disease. Lancet 373:1550–1561PubMedPubMedCentralCrossRefGoogle Scholar
  46. Floess S et al (2007) Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol 5:e38PubMedPubMedCentralCrossRefGoogle Scholar
  47. Fontenot JD et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341PubMedCrossRefGoogle Scholar
  48. Fu J et al (2007) Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients. Gastroenterology 132:2328–2339PubMedCrossRefGoogle Scholar
  49. Gobert M et al (2009) Regulatory T cells recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Res 69:2000–2009PubMedCrossRefGoogle Scholar
  50. Gotot J et al (2012) Regulatory T cells use programmed death 1 ligands to directly suppress autoreactive B cells in vivo. Proc Natl Acad Sci U S A 109:10468–10473PubMedPubMedCentralCrossRefGoogle Scholar
  51. Green EA, Gorelik L, McGregor CM, Tran EH, Flavell RA (2003) CD4+CD25+ T regulatory cells control anti-islet CD8+ T cells through TGF-beta-TGF-beta receptor interactions in type 1 diabetes. Proc Natl Acad Sci U S A 100:10878–10883PubMedPubMedCentralCrossRefGoogle Scholar
  52. Grohmann U et al (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3:1097–1101PubMedCrossRefGoogle Scholar
  53. Grossman WJ et al (2004a) Differential expression of granzymes A and B in human cytotoxic lymphocyte subsets and T regulatory cells. Blood 104:2840–2848PubMedCrossRefGoogle Scholar
  54. Grossman WJ et al (2004b) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601PubMedCrossRefGoogle Scholar
  55. Guo Z et al (2008) CD4+CD25+ regulatory T cells in the small intestinal lamina propria show an effector/memory phenotype. Int Immunol 20:307–315PubMedCrossRefGoogle Scholar
  56. Hahn BH, Singh RP, La Cava A, Ebling FM (2005) Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors. J Immunol 175:7728–7737PubMedCrossRefGoogle Scholar
  57. Han KL et al (2013) Adenosine A(2)A receptor agonist-mediated increase in donor-derived regulatory T cells suppresses development of graft-versus-host disease. J Immunol 190:458–468PubMedCrossRefGoogle Scholar
  58. Hanash AM, Levy RB (2005) Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 105:1828–1836PubMedCrossRefGoogle Scholar
  59. Hill GR, Ferrara JL (2000) The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 95:2754–2759PubMedGoogle Scholar
  60. Hiraoka N, Onozato K, Kosuge T, Hirohashi S (2006) Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res 12:5423–5434PubMedCrossRefPubMedCentralGoogle Scholar
  61. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196:389–399PubMedPubMedCentralCrossRefGoogle Scholar
  62. Hoffmann P, Eder R, Kunz-Schughart LA, Andreesen R, Edinger M (2004) Large-scale in vitro expansion of polyclonal human CD4(+)CD25 high regulatory T cells. Blood 104:895–903PubMedCrossRefPubMedCentralGoogle Scholar
  63. Hsieh CS et al (2004) Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors. Immunity 21:267–277PubMedCrossRefPubMedCentralGoogle Scholar
  64. Huang CT et al (2004) Role of LAG-3 in regulatory T cells. Immunity 21:503–513PubMedCrossRefGoogle Scholar
  65. Huber S et al (2004) Cutting edge: TGF-beta signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J Immunol 173:6526–6531PubMedCrossRefGoogle Scholar
  66. Inoue Y, Fuji S, Tanosaki R, Fukuda T (2016) Pretransplant mogamulizumab against ATLL might increase the risk of acute GVHD and non-relapse mortality. Bone Marrow Transplant 51:725–727. CrossRefPubMedGoogle Scholar
  67. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S et al (2012) Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 30:837–842PubMedCrossRefGoogle Scholar
  68. Janssens W et al (2003) CD4+CD25+ T cells lyse antigen-presenting B cells by Fas-Fas ligand interaction in an epitope-specific manner. J Immunol 171:4604–4612PubMedCrossRefGoogle Scholar
  69. Jenq RR, van den Brink MR (2010) Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10:213–221PubMedCrossRefGoogle Scholar
  70. Joffre O, Gorsse N, Romagnoli P, Hudrisier D, van Meerwijk JP (2004) Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. Blood 103:4216–4221PubMedPubMedCentralCrossRefGoogle Scholar
  71. Jones SC, Murphy GF, Korngold R (2003) Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant 9:243–256PubMedCrossRefPubMedCentralGoogle Scholar
  72. Kim YM, Sachs T, Asavaroengchai W, Bronson R, Sykes M (2003) Graft-versus-host disease can be separated from graft-versus-lymphoma effects by control of lymphocyte trafficking with FTY720. J Clin Invest 111:659–669PubMedPubMedCentralCrossRefGoogle Scholar
  73. Kitazawa Y et al (2009) Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases. Cell Transplant 18:627–637PubMedCrossRefGoogle Scholar
  74. Kloosterman TC, Martens AC, van Bekkum DW, Hagenbeek A (1995) Graft-versus-leukemia in rat MHC-mismatched bone marrow transplantation is merely an allogeneic effect. Bone Marrow Transplant 15:583–590PubMedPubMedCentralGoogle Scholar
  75. Ko K et al (2005) Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med 202:885–891PubMedPubMedCentralCrossRefGoogle Scholar
  76. Koch MA et al (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602PubMedPubMedCentralCrossRefGoogle Scholar
  77. Koreth J, Matsuoka K, Kim HT, McDonough SM, Bindra B, Alyea EP et al (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365:2055–2066PubMedPubMedCentralCrossRefGoogle Scholar
  78. Koreth J, Kim HT, Jones KT, Lange PB, Reynolds CG, Chammas MJ et al (2016) Efficacy, durability, and response predictors of low-dose interleukin-2 therapy for chronic graft vs. host disease. Blood 128:130–137. pii: blood-2016-02-702852PubMedPubMedCentralCrossRefGoogle Scholar
  79. Levine AG, Arvey A, Jin W, Rudensky AY (2014) Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 15:1070–1078PubMedPubMedCentralCrossRefGoogle Scholar
  80. Lewkowicz P, Lewkowicz N, Sasiak A, Tchorzewski H (2006) Lipopolysaccharide-activated CD4+CD25+ T regulatory cells inhibit neutrophil function and promote their apoptosis and death. J Immunol 177:7155–7163PubMedCrossRefGoogle Scholar
  81. Lewkowicz N, Klink M, Mycko MP, Lewkowicz P (2013) Neutrophil--CD4+CD25+ T regulatory cell interactions: a possible new mechanism of infectious tolerance. Immunobiology 218:455–464PubMedCrossRefGoogle Scholar
  82. Li J et al (2015) HY-specific induced regulatory T cells display high specificity and efficacy in the prevention of acute graft-versus-host disease. J Immunol 195:717–725PubMedPubMedCentralCrossRefGoogle Scholar
  83. Liang B et al (2008) Regulatory T cells inhibit dendritic cells by lymphocyte activation gene-3 engagement of MHC class II. J Immunol 180:5916–5926PubMedCrossRefGoogle Scholar
  84. Lim HW, Hillsamer P, Banham AH, Kim CH (2005) Cutting edge: direct suppression of B cells by CD4+ CD25+ regulatory T cells. J Immunol 175:4180–4183PubMedCrossRefGoogle Scholar
  85. Lim DG et al (2010) Impact of immunosuppressants on the therapeutic efficacy of in vitro-expanded CD4+CD25+Foxp3+ regulatory T cells in allotransplantation. Transplantation 89:928–936PubMedCrossRefGoogle Scholar
  86. Lin MT et al (2003) Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med 349:2201–2210PubMedCrossRefGoogle Scholar
  87. Malek TR (2008) The biology of interleukin-2. Annu Rev Immunol 26:453–479PubMedCrossRefGoogle Scholar
  88. Malek TR, Castro I (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33:153–165PubMedPubMedCentralCrossRefGoogle Scholar
  89. Matheu MP et al (2015) Imaging regulatory T cell dynamics and CTLA4-mediated suppression of T cell priming. Nat Commun 6:6219PubMedPubMedCentralCrossRefGoogle Scholar
  90. Mavin E et al (2012) Regulatory T cells inhibit CD8(+) T-cell tissue invasion in human skin graft-versus-host reactions. Transplantation 94:456–464PubMedCrossRefGoogle Scholar
  91. Mellor AL, Munn DH (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 4:762–774PubMedCrossRefPubMedCentralGoogle Scholar
  92. Mempel TR et al (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129–141PubMedCrossRefGoogle Scholar
  93. Misra N, Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172:4676–4680PubMedCrossRefGoogle Scholar
  94. Munn DH (2011) Indoleamine 2,3-dioxygenase, Tregs and cancer. Curr Med Chem 18:2240–2246PubMedCrossRefGoogle Scholar
  95. Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194:629–644PubMedPubMedCentralCrossRefGoogle Scholar
  96. Nguyen VH et al (2007) In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood 109:2649–2656PubMedCrossRefGoogle Scholar
  97. Nishimori H, Maeda Y, Teshima T, Sugiyama H, Kobayashi K, Yamasuji Y et al (2012) Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. Blood 119:285–295PubMedCrossRefGoogle Scholar
  98. Pandiyan P, Zheng L, Ishihara S, Reed J, Lenardo MJ (2007) CD4+CD25+Foxp3+ regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4+ T cells. Nat Immunol 8:1353–1362PubMedCrossRefGoogle Scholar
  99. Peng G et al (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309:1380–1384PubMedCrossRefGoogle Scholar
  100. Phan GQ et al (2003) Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A 100:8372–8377PubMedPubMedCentralCrossRefGoogle Scholar
  101. Pierini A et al (2015) Donor requirements for regulatory T cell suppression of murine graft-versus-host disease. J Immunol 195:347–355PubMedPubMedCentralCrossRefGoogle Scholar
  102. Qureshi OS et al (2011) Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332:600–603PubMedPubMedCentralCrossRefGoogle Scholar
  103. Reddy P et al (2005) A crucial role for antigen-presenting cells and alloantigen expression in graft-versus-leukemia responses. Nat Med 11:1244–1249PubMedCrossRefGoogle Scholar
  104. Richards H et al (2010) Novel role of regulatory T cells in limiting early neutrophil responses in skin. Immunology 131:583–592PubMedPubMedCentralCrossRefGoogle Scholar
  105. Roncarolo MG, Gregori S, Bacchetta R, Battaglia M (2014) Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Curr Top Microbiol Immunol 380:39–68PubMedGoogle Scholar
  106. Rubtsov YP et al (2008) Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity 28:546–558PubMedCrossRefGoogle Scholar
  107. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164PubMedGoogle Scholar
  108. Sakaguchi S et al (2006) Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 212:8–27PubMedCrossRefGoogle Scholar
  109. Salomon B, Bluestone JA (2001) Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol 19:225–252PubMedCrossRefGoogle Scholar
  110. Sarween N et al (2004) CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. J Immunol 173:2942–2951PubMedCrossRefPubMedCentralGoogle Scholar
  111. Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A (2003) CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies: possible involvement of regulatory T cells in disease progression. Cancer 98:1089–1099PubMedCrossRefGoogle Scholar
  112. Sauer S et al (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U S A 105:7797–7802PubMedPubMedCentralCrossRefGoogle Scholar
  113. Sawamukai N et al (2012) Cell-autonomous role of TGFbeta and IL-2 receptors in CD4+ and CD8+ inducible regulatory T-cell generation during GVHD. Blood 119:5575–5583PubMedPubMedCentralCrossRefGoogle Scholar
  114. Schneidawind D, Pierini A, Negrin RS (2013) Regulatory T cells and natural killer T cells for modulation of GVHD following allogeneic hematopoietic cell transplantation. Blood 122:3116–3121PubMedPubMedCentralCrossRefGoogle Scholar
  115. Schneider H, Valk E, da Rocha Dias S, Wei B, Rudd CE (2005) CTLA-4 up-regulation of lymphocyte function-associated antigen 1 adhesion and clustering as an alternate basis for coreceptor function. Proc Natl Acad Sci U S A 102:12861–12866PubMedPubMedCentralCrossRefGoogle Scholar
  116. Schreck S et al (2009) Prognostic impact of tumour-infiltrating Th2 and regulatory T cells in classical Hodgkin lymphoma. Hematol Oncol 27:31–39PubMedCrossRefPubMedCentralGoogle Scholar
  117. Schwab L et al (2014) Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat Med 20:648–654PubMedCrossRefGoogle Scholar
  118. Scotta C et al (2016) Impact of immunosuppressive drugs on the therapeutic efficacy of ex vivo expanded human regulatory T cells. Haematologica 101:91–100PubMedPubMedCentralCrossRefGoogle Scholar
  119. Semple K, Yu Y, Wang D, Anasetti C, Yu XZ (2011) Efficient and selective prevention of GVHD by antigen-specific induced Tregs via linked-suppression in mice. Biol Blood Marrow Transplant 17:309–318PubMedPubMedCentralCrossRefGoogle Scholar
  120. Setoguchi R, Hori S, Takahashi T, Sakaguchi S (2005) Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 201:723–735PubMedPubMedCentralCrossRefGoogle Scholar
  121. Sharfe N, Dadi HK, Shahar M, Roifman CM (1997) Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. Proc Natl Acad Sci U S A 94:3168–3171PubMedPubMedCentralCrossRefGoogle Scholar
  122. Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S (2002) Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 3:135–142PubMedCrossRefGoogle Scholar
  123. Shin HJ et al (2011) Rapamycin and IL-2 reduce lethal acute graft-versus-host disease associated with increased expansion of donor type CD4+CD25+Foxp3+ regulatory T cells. Blood 118:2342–2350PubMedPubMedCentralCrossRefGoogle Scholar
  124. Smigiel KS et al (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121–136PubMedPubMedCentralCrossRefGoogle Scholar
  125. Soler D et al (2006) CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. J Immunol 177:6940–6951PubMedCrossRefGoogle Scholar
  126. Szczepanski MJ et al (2009) Increased frequency and suppression by regulatory T cells in patients with acute myelogenous leukemia. Clin Cancer Res 15:3325–3332PubMedPubMedCentralCrossRefGoogle Scholar
  127. Taams LS et al (2005) Modulation of monocyte/macrophage function by human CD4+CD25+ regulatory T cells. Hum Immunol 66:222–230PubMedPubMedCentralCrossRefGoogle Scholar
  128. Tadokoro CE et al (2006) Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med 203:505–511PubMedPubMedCentralCrossRefGoogle Scholar
  129. Takahashi T et al (1998) Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980PubMedCrossRefGoogle Scholar
  130. Tang Q et al (2006) Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7:83–92PubMedCrossRefGoogle Scholar
  131. Tao H et al (2012) Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells. Lung Cancer 75:95–101PubMedCrossRefGoogle Scholar
  132. Tawara I et al (2012) Donor- but not host-derived interleukin-10 contributes to the regulation of experimental graft-versus-host disease. J Leukoc Biol 91:667–675PubMedPubMedCentralCrossRefGoogle Scholar
  133. Taylor PA, Noelle RJ, Blazar BR (2001) CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med 193:1311–1318PubMedPubMedCentralCrossRefGoogle Scholar
  134. Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499PubMedCrossRefGoogle Scholar
  135. Taylor PA et al (2004) L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 104:3804–3812PubMedCrossRefGoogle Scholar
  136. Theil A, Tuve S, Oelschlägel U, Maiwald A, Döhler D, Oßmann D et al (2015) Adoptive transfer of allogeneic regulatory T cells into patients with chronic graft-versus-host disease. Cytotherapy 17:473–486PubMedCrossRefGoogle Scholar
  137. Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190PubMedCrossRefGoogle Scholar
  138. Tivol EA et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547PubMedCrossRefGoogle Scholar
  139. Trenado A et al (2003) Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest 112:1688–1696PubMedPubMedCentralCrossRefGoogle Scholar
  140. Tresoldi E et al (2011) Stability of human rapamycin-expanded CD4+CD25+ T regulatory cells. Haematologica 96:1357–1365PubMedPubMedCentralCrossRefGoogle Scholar
  141. Trzonkowski P, Szmit E, Mysliwska J, Dobyszuk A, Mysliwski A (2004) CD4+CD25+ T regulatory cells inhibit cytotoxic activity of T CD8+ and NK lymphocytes in the direct cell-to-cell interaction. Clin Immunol 112:258–267PubMedCrossRefGoogle Scholar
  142. Veerapathran A, Pidala J, Beato F, Yu XZ, Anasetti C (2011) Ex vivo expansion of human Tregs specific for alloantigens presented directly or indirectly. Blood 118:5671–5680PubMedPubMedCentralCrossRefGoogle Scholar
  143. Vence L et al (2007) Circulating tumor antigen-specific regulatory T cells in patients with metastatic melanoma. Proc Natl Acad Sci U S A 104:20884–20889PubMedPubMedCentralCrossRefGoogle Scholar
  144. Venet F et al (2006) Human CD4+CD25+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism. J Immunol 177:6540–6547PubMedCrossRefPubMedCentralGoogle Scholar
  145. Venturi GM, Conway RM, Steeber DA, Tedder TF (2007) CD25+CD4+ regulatory T cell migration requires L-selectin expression: L-selectin transcriptional regulation balances constitutive receptor turnover. J Immunol 178:291–300PubMedCrossRefPubMedCentralGoogle Scholar
  146. Walsh PT et al (2006) PTEN inhibits IL-2 receptor-mediated expansion of CD4+ CD25+ Tregs. J Clin Invest 116:2521–2531PubMedPubMedCentralGoogle Scholar
  147. Weiner HL (2001) Induction and mechanism of action of transforming growth factor-beta-secreting Th3 regulatory cells. Immunol Rev 182:207–214PubMedCrossRefPubMedCentralGoogle Scholar
  148. Wildin RS et al (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27:18–20PubMedCrossRefGoogle Scholar
  149. Wu T et al (2012) Immunosuppressive drugs on inducing Ag-specific CD4(+)CD25(+)Foxp3(+) Treg cells during immune response in vivo. Transpl Immunol 27:30–38PubMedCrossRefGoogle Scholar
  150. Xu A et al (2016) TGF-beta-induced regulatory T cells directly suppress B cell responses through a noncytotoxic mechanism. J Immunol 196(9):3631–3641PubMedPubMedCentralCrossRefGoogle Scholar
  151. Yan Y et al (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185:5953–5961PubMedPubMedCentralCrossRefGoogle Scholar
  152. Yang ZZ, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM (2006) Attenuation of CD8(+) T-cell function by CD4(+)CD25(+) regulatory T cells in B-cell non-Hodgkin’s lymphoma. Cancer Res 66:10145–10152PubMedPubMedCentralCrossRefGoogle Scholar
  153. Yu F, Sharma S, Edwards J, Feigenbaum L, Zhu J (2015) Dynamic expression of transcription factors T-bet and GATA-3 by regulatory T cells maintains immunotolerance. Nat Immunol 16:197–206PubMedCrossRefGoogle Scholar
  154. Yurchenko E et al (2006) CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence. J Exp Med 203:2451–2460PubMedPubMedCentralCrossRefGoogle Scholar
  155. Zeiser R, Nguyen VH, Beilhack A, Buess M, Schulz S, Baker J, Contag CH, Negrin RS (2006) Inhibition of CD4+CD25+ regulatory T cell function by calcineurin dependent interleukin-2 production. Blood 108:390–399PubMedPubMedCentralCrossRefGoogle Scholar
  156. Zeiser R et al (2007) Early CD30 signaling is critical for adoptively transferred CD4+CD25+ regulatory T cells in prevention of acute graft-versus-host disease. Blood 109:2225–2233PubMedPubMedCentralCrossRefGoogle Scholar
  157. Zeiser R et al (2008) Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111:453–462PubMedPubMedCentralCrossRefGoogle Scholar
  158. Zeiser R, Penack O, Holler E, Idzko M (2011) Danger signals activating innate immunity in graft-versus-host disease. J Mol Med (Berl) 89:833–845CrossRefGoogle Scholar
  159. Zhang P et al (2013) Induced regulatory T cells promote tolerance when stabilized by rapamycin and IL-2 in vivo. J Immunol 191:5291–5303PubMedCrossRefGoogle Scholar
  160. Zhao DM, Thornton AM, DiPaolo RJ, Shevach EM (2006) Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 107:3925–3932PubMedPubMedCentralCrossRefGoogle Scholar
  161. Zheng Y et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Hematology and OncologyAlbert Ludwig University FreiburgFreiburgGermany

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