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Functionally Defined T Cell Subsets in Transplantation Biology and Therapy: Regulatory T Cells and Th2 Cells

  • Daniel Fowler
  • Petra Hoffmann
  • Matthias Edinger
Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 144)

Regulatory T Cells

Biology of CD4+CD25+ Regulatory T Cells (Treg Cells)

Peripheral tolerance mechanisms include deletion by activation induced cell death, anergy and dominant suppression. Although the important contribution of suppression for the maintenance of peripheral T-cell tolerance was repeatedly proven in experimental systems, it was discredited for many years as no defined suppressor cell population could be identified. In 1995, Sakaguchi and coworkers rejuvenated interest in T-cell-mediated immunosuppression when they showed that thymectomy in neonatal mice caused autoimmunity that could be prevented by adoptive transfer of CD25-coexpressing CD4+ T cells isolated from adult animals [1]. These findings advanced the field in several aspects: (1) For the first time, phenotypic markers (CD4+CD25+) identified a cell population endowed with potent suppressive activity; (2) the suppressive cell population seemed to be thymus-derived; (3) its export from the thymus seemed to be...

Keywords

Hematopoietic Stem Cell Transplantation Treg Cell Acute GvHD Allogeneic Hematopoietic Stem Cell Transplantation Chronic GvHD 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Sakaguchi S. Sakaguchi N. Asano M. Itoh M. Toda M. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995;155:1151–64.PubMedGoogle Scholar
  2. 2.
    Bluestone JA. Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253–7.PubMedGoogle Scholar
  3. 3.
    Chen W. Jin W. Hardegen N, 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. 2003;198:1875–86.PubMedGoogle Scholar
  4. 4.
    Fontenot JD. Gavin MA. Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedGoogle Scholar
  5. 5.
    Brunkow ME. Jeffery EW. Hjerrild KA, et al. Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet. 2001;27:68–73.PubMedGoogle Scholar
  6. 6.
    Bennett CL. Christie J. Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–1.PubMedGoogle Scholar
  7. 7.
    Fontenot JD. Rasmussen JP. Williams LM. Dooley JL. Farr AG. Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 2005;22:329–41.PubMedGoogle Scholar
  8. 8.
    Lahl K. Loddenkemper C. Drouin C, et al. Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007;204:57–63.PubMedGoogle Scholar
  9. 9.
    Williams LM. Rudensky AY. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nat Immunol. 2007;8:277–84.PubMedGoogle Scholar
  10. 10.
    Wan YY. Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445:766–70.PubMedGoogle Scholar
  11. 11.
    Baecher-Allan C. Brown JA. Freeman GJ. Hafler DA. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.PubMedGoogle Scholar
  12. 12.
    Wing K. Suri-Payer E. Rudin A. CD4+CD25+ -regulatory T cells from mouse to man. Scand J Immunol. 2005;62:1–15.PubMedGoogle Scholar
  13. 13.
    Liu W. Putnam AL. Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701–11.PubMedGoogle Scholar
  14. 14.
    Seddiki N. Santner-Nanan B. Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203:1693–1700.PubMedGoogle Scholar
  15. 15.
    Pacholczyk R. Kern J. Singh N. Iwashima M. Kraj P. Ignatowicz L. Nonself-antigens are the cognate specificities of Foxp3+ regulatory T cells. Immunity 2007;27:493–504.PubMedGoogle Scholar
  16. 16.
    Wong J. Obst R. Correia-Neves M. Losyev G. Mathis D. Benoist C. Adaptation of TCR repertoires to self-peptides in regulatory and nonregulatory CD4+ T cells. J Immunol. 2007;178:7032–41.PubMedGoogle Scholar
  17. 17.
    Valmori D. Merlo A. Souleimanian NE. Hesdorffer CS. Ayyoub M. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Invest. 2005;115:1953–62.PubMedGoogle Scholar
  18. 18.
    Hoffmann P. Eder R. Boeld TJ, et al. Only the CD45RA+ subpopulation of CD4+CD25high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006;108:4260–7.PubMedGoogle Scholar
  19. 19.
    Thornton AM. Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164:183–90.PubMedGoogle Scholar
  20. 20.
    Su L. Creusot RJ. Gallo EM, et al. Murine CD4+CD25+ regulatory T cells fail to undergo chromatin remodeling across the proximal promoter region of the IL-2 gene. J Immunol. 2004;173:4994–5001.PubMedGoogle Scholar
  21. 21.
    Bensinger SJ. Walsh PT. Zhang J, et al. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J Immunol. 2004;172:5287–96.PubMedGoogle Scholar
  22. 22.
    Hickman SP. Yang J. Thomas RM. Wells AD. Turka LA. Defective activation of protein kinase C and Ras-ERK pathways limits IL-2 production and proliferation by CD4+CD25+ regulatory T cells. J Immunol. 2006;177:2186–94.PubMedGoogle Scholar
  23. 23.
    Fontenot JD. Rasmussen JP. Gavin MA. Rudensky AY. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat Immunol. 2005;6:1142–51.PubMedGoogle Scholar
  24. 24.
    Klein L. Khazaie K, von Boehmer H. In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci USA. 2003;100:8886–91.Google Scholar
  25. 25.
    Fisson S. Darrasse-Jeze G. Litvinova E, et al. Continuous activation of autoreactive CD4+CD25+ regulatory T cells in the steady state. J Exp Med. 2003;198:737–46.PubMedGoogle Scholar
  26. 26.
    Earle KE. Tang Q. Zhou X, et al. In vitro expanded human CD4+CD25+ regulatory T cells suppress effector T cell proliferation. Clin Immunol. 2005;115:3–9.PubMedGoogle Scholar
  27. 27.
    Hoffmann P. Eder R. Kunz-Schughart LA. Andreesen R. Edinger M. Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 2004;104:895–903.PubMedGoogle Scholar
  28. 28.
    Hoffmann P. Boeld TJ. Eder R, et al. Isolation of CD4(+)CD25(+) Regulatory T Cells for Clinical Trials. Biol Blood Marrow Transplant. 2006;12:267–74.PubMedGoogle Scholar
  29. 29.
    Thornton AM. Shevach EM. CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production. J Exp Med. 1998;188:287–96.PubMedGoogle Scholar
  30. 30.
    Zhao DM. Thornton AM. DiPaolo RJ. Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 2006;107:3925–32.PubMedGoogle Scholar
  31. 31.
    Romagnani C. Della Chiesa M. Kohler S, et al. Activation of human NK cells by plasmacytoid dendritic cells and its modulation by CD4+ T helper cells and CD4+ CD25hi T regulatory cells. Eur J Immunol. 2005;35:2452–8.PubMedGoogle Scholar
  32. 32.
    Misra N. Bayry J. Lacroix-Desmazes S. Kazatchkine MD. Kaveri SV. Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol. 2004;172:4676–80.PubMedGoogle Scholar
  33. 33.
    von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6:338–44.Google Scholar
  34. 34.
    Nakamura K. Kitani A. Fuss I, et al. TGF-beta 1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172:834–42.PubMedGoogle Scholar
  35. 35.
    Birebent B. Lorho R. Lechartier H, et al. Suppressive properties of human CD4+CD25+ regulatory T cells are dependent on CTLA-4 expression. Eur J Immunol. 2004;34:3485–96.PubMedGoogle Scholar
  36. 36.
    Bopp T. Becker C. Klein M, et al. Cyclic adenosine monophosphate is a key component of regulatory T cell-mediated suppression. J Exp Med. 2007;204:1303–10.PubMedGoogle Scholar
  37. 37.
    Deaglio S. Dwyer KM. Gao W, et al. Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med. 2007;204:1257–65.PubMedGoogle Scholar
  38. 38.
    Bodor J. Fehervari Z. Diamond B. Sakaguchi S. ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells. Eur J Immunol. 2007;37:884–95.PubMedGoogle Scholar
  39. 39.
    de la Rosa M. Rutz S. Dorninger H. Scheffold A. Interleukin-2 is essential for CD4+CD25+ regulatory T cell function. Eur J Immunol. 2004;34:2480–8.PubMedGoogle Scholar
  40. 40.
    Pandiyan P. Zheng L. Ishihara S. Reed J. Lenardo MJ. CD4(+)CD25(+)Foxp3(+) regulatory T cells induce cytokine deprivation-mediated apoptosis of effector CD4(+) T cells. Nat Immunol. 2007;8:1353–62.PubMedGoogle Scholar
  41. 41.
    Cao X. Cai SF. Fehniger TA, et al. Granzyme B and perforin are important for regulatory T cell-mediated suppression of tumor clearance. Immunity 2007;27:635–46.PubMedGoogle Scholar
  42. 42.
    Rudensky AY. Campbell DJ. In vivo sites and cellular mechanisms of T reg cell-mediated suppression. J Exp Med. 2006;203:489–92.PubMedGoogle Scholar
  43. 43.
    Edinger M. Hoffmann P. Ermann J, et al. CD4(+)CD25(+) regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144–50.PubMedGoogle Scholar
  44. 44.
    Tang Q. Adams JY. Tooley AJ, et al. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol. 2006;7:83–92.PubMedGoogle Scholar
  45. 45.
    Tadokoro CE. Shakhar G. Shen S, et al. Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo. J Exp Med. 2006;203:505–11.PubMedGoogle Scholar
  46. 46.
    Chen ML. Pittet MJ. Gorelik L, et al. Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proc Natl Acad Sci USA. 2005;102:419–24.Google Scholar
  47. 47.
    Chen Z. Herman AE. Matos M. Mathis D. Benoist C. Where CD4+CD25+ T reg cells impinge on autoimmune diabetes. J Exp Med. 2005;202:1387–97.PubMedGoogle Scholar
  48. 48.
    Siegmund K. Feuerer M. Siewert C, et al. Migration matters: regulatory T-cell compartmentalization determines suppressive activity in vivo. Blood 2005;106:3097–104.PubMedGoogle Scholar
  49. 49.
    Waldmann H. Adams E. Fairchild P. Cobbold S. Infectious tolerance and the long-term acceptance of transplanted tissue. Immunol Rev. 2006;212:301–13.PubMedGoogle Scholar
  50. 50.
    Roncarolo MG. Gregori S. Battaglia M. Bacchetta R. Fleischhauer K. Levings MK. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol Rev. 2006;212:28–50.PubMedGoogle Scholar
  51. 51.
    Walker MR. Kasprowicz DJ. Gersuk VH, et al. Induction of FoxP3 and acquisition of T regulatory activity by stimulated human CD4+CD25– T cells. J Clin Invest. 2003;112:1437–43.PubMedGoogle Scholar
  52. 52.
    Kretschmer K. Apostolou I. Hawiger D. Khazaie K. Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6:1219–27.PubMedGoogle Scholar
  53. 53.
    Floess S. Freyer J. Siewert C, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5:e38.PubMedGoogle Scholar
  54. 54.
    Fantini MC. Becker C. Monteleone G. Pallone F. Galle PR. Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25– T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172:5149–53.PubMedGoogle Scholar
  55. 55.
    Tran DQ. Ramsey H. Shevach EM. Induction of FOXP3 expression in naive human CD4+FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood 2007;110:2983–90.PubMedGoogle Scholar
  56. 56.
    Pillai V. Karandikar NJ. Human regulatory T cells: a unique, stable thymic subset or a reversible peripheral state of differentiation? Immunol Lett. 2007;114:9–15.PubMedGoogle Scholar
  57. 57.
    Sun CM. Hall JA. Blank RB, et al. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204:1775–85.PubMedGoogle Scholar
  58. 58.
    Coombes JL. Siddiqui KR. Arancibia-Carcamo CV, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757–64.PubMedGoogle Scholar
  59. 59.
    Benson MJ. Pino-Lagos K. Rosemblatt M. Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204:1765–74.PubMedGoogle Scholar
  60. 60.
    Weaver CT. Harrington LE. Mangan PR. Gavrieli M. Murphy KM. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006;24:677–88.PubMedGoogle Scholar
  61. 61.
    Cua DJ. Sherlock J. Chen Y, et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 2003;421:744–8.PubMedGoogle Scholar
  62. 62.
    Veldhoen M. Hocking RJ. Atkins CJ. Locksley RM. Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 2006;24:179–89.PubMedGoogle Scholar
  63. 63.
    Mangan PR. Harrington LE. O’Quinn DB, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 2006;441:231–4.PubMedGoogle Scholar
  64. 64.
    Bettelli E. Carrier Y. Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 2006;441:235–8.PubMedGoogle Scholar
  65. 65.
    Stockinger B. Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19:281–6.PubMedGoogle Scholar
  66. 66.
    Ivanov, II. McKenzie BS. Zhou L, et al. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 2006;126:1121–33.PubMedGoogle Scholar
  67. 67.
    Korn T. Bettelli E. Gao W, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007;448:484–7.PubMedGoogle Scholar
  68. 68.
    Bettelli E. Korn T. Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol. 2007;19:652–7.PubMedGoogle Scholar
  69. 69.
    Hoffmann P. Ermann J. Edinger M. Fathman CG. Strober S. Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med. 2002;196:389–99.PubMedGoogle Scholar
  70. 70.
    Cohen JL. Trenado A. Vasey D. Klatzmann D. Salomon BL. CD4(+)CD25(+) immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med. 2002;196:401–6.PubMedGoogle Scholar
  71. 71.
    Taylor PA. Friedman TM. Korngold R. Noelle RJ. Blazar BR. Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40:CD40L costimulatory pathway results in the generation of a potent immune regulatory cell. Blood 2002;99:4601–9.PubMedGoogle Scholar
  72. 72.
    Taylor PA. Lees CJ. Blazar BR. The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 2002;99:3493–9.PubMedGoogle Scholar
  73. 73.
    Jones SC. Murphy GF. Korngold R. Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4(+)25(+) T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant. 2003;9:243–56.PubMedGoogle Scholar
  74. 74.
    Moore KW, de Waal Malefyt R. Coffman RL. O’Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.PubMedGoogle Scholar
  75. 75.
    Nguyen VH. Zeiser R. Dasilva DL, et al. In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood 2007;109:2649–56.PubMedGoogle Scholar
  76. 76.
    Hanash AM. Levy RB. Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 2005;105:1828–36.PubMedGoogle Scholar
  77. 77.
    Steiner D. Brunicki N. Bachar-Lustig E. Taylor PA. Blazar BR. Reisner Y. Overcoming T cell-mediated rejection of bone marrow allografts by T-regulatory cells: synergism with veto cells and rapamycin. Exp Hematol. 2006;34:802–8.PubMedGoogle Scholar
  78. 78.
    Trenado A. Charlotte F. Fisson S, et al. 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. 2003;112:1688–96.PubMedGoogle Scholar
  79. 79.
    Nguyen VH. Shashidhar S. Chang DS, et al. The impact of regulatory T cells on T-cell immunity following hematopoietic cell transplantation. Blood 2008;111:945–53.PubMedGoogle Scholar
  80. 80.
    Taylor PA. Panoskaltsis-Mortari A. Swedin JM, et al. L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 2004;104:3804–12.PubMedGoogle Scholar
  81. 81.
    Ermann J. Hoffmann P. Edinger M, et al. Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 2005;105:2220–6.PubMedGoogle Scholar
  82. 82.
    Shlomchik WD. Couzens MS. Tang CB, et al. Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 1999;285:412–5.PubMedGoogle Scholar
  83. 83.
    Wysocki CA. Jiang Q. Panoskaltsis-Mortari A, et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 2005;106:3300–7.PubMedGoogle Scholar
  84. 84.
    Mottet C. Uhlig HH. Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003;170:3939–43.PubMedGoogle Scholar
  85. 85.
    Johnson BD. Truitt RL. Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 1995;85:3302–12.PubMedGoogle Scholar
  86. 86.
    Johnson BD. Becker EE. LaBelle JL. Truitt RL. Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy. J Immunol. 1999;163:6479–87.PubMedGoogle Scholar
  87. 87.
    Johnson BD. Konkol MC. Truitt RL. CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant. 2002;8:525–35.PubMedGoogle Scholar
  88. 88.
    Stanzani M. Martins SL. Saliba RM, et al. CD25 expression on donor CD4+ or CD8+ T cells is associated with an increased risk for graft-versus-host disease after HLA-identical stem cell transplantation in humans. Blood 2004;103:1140–6.PubMedGoogle Scholar
  89. 89.
    Rezvani K. Mielke S. Ahmadzadeh M, et al. High donor FOXP3-positive regulatory T-cell (Treg) content is associated with a low risk of GVHD following HLA-matched allogeneic SCT. Blood 2006;108:1291–7.PubMedGoogle Scholar
  90. 90.
    Pabst C. Schirutschke H. Ehninger G. Bornhauser M. Platzbecker U. The graft content of donor T cells expressing gamma delta TCR+ and CD4+foxp3+ predicts the risk of acute graft versus host disease after transplantation of allogeneic peripheral blood stem cells from unrelated donors. Clin Cancer Res. 2007;13:2916–22.PubMedGoogle Scholar
  91. 91.
    Wolf D. Wolf AM. Fong D, et al. Regulatory T-cells in the graft and the risk of acute graft-versus-host disease after allogeneic stem cell transplantation. Transplantation 2007;83:1107–13.PubMedGoogle Scholar
  92. 92.
    Martin PJ. Pei J. Gooley T, et al. Evaluation of a CD25-specific immunotoxin for prevention of graft-versus-host disease after unrelated marrow transplantation. Biol Blood Marrow Transplant. 2004;10:552–60.PubMedGoogle Scholar
  93. 93.
    Lee SJ. Zahrieh D. Agura E, et al. Effect of up-front daclizumab when combined with steroids for the treatment of acute graft-versus-host disease: results of a randomized trial. Blood 2004;104:1559–64.PubMedGoogle Scholar
  94. 94.
    Miura Y. Thoburn CJ. Bright EC, et al. Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 2004;104:2187–93.PubMedGoogle Scholar
  95. 95.
    Schneider M. Munder M. Karakhanova S. Ho AD. Goerner M. The initial phase of graft-versus-host disease is associated with a decrease of CD4+CD25+ regulatory T cells in the peripheral blood of patients after allogeneic stem cell transplantation. Clin Lab Haematol. 2006;28:382–90.PubMedGoogle Scholar
  96. 96.
    Mielke S. Rezvani K. Savani BN, et al. Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantation in elderly patients and association with acute graft-versus-host disease. Blood 2007;110:1689–97.PubMedGoogle Scholar
  97. 97.
    Sanchez J. Casano J. Alvarez MA, et al. Kinetic of regulatory CD25high and activated CD134+ (OX40) T lymphocytes during acute and chronic graft-versus-host disease after allogeneic bone marrow transplantation. Br J Haematol. 2004;126:697–703.PubMedGoogle Scholar
  98. 98.
    Arimoto K. Kadowaki N. Ishikawa T. Ichinohe T. Uchiyama T. FOXP3 expression in peripheral blood rapidly recovers and lacks correlation with the occurrence of graft-versus-host disease after allogeneic stem cell transplantation. Int J Hematol. 2007;85:154–62.PubMedGoogle Scholar
  99. 99.
    Rieger K. Loddenkemper C. Maul J, et al. Mucosal FOXP3+ regulatory T cells are numerically deficient in acute and chronic GvHD. Blood 2006;107:1717–23.PubMedGoogle Scholar
  100. 100.
    Clark FJ. Gregg R. Piper K, et al. Chronic graft-versus-host disease is associated with increased numbers of peripheral blood CD4+CD25high regulatory T cells. Blood 2004;103:2410–6.PubMedGoogle Scholar
  101. 101.
    Zorn E. Kim HT. Lee SJ, et al. Reduced frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-versus-host disease. Blood 2005;106:2903–11.PubMedGoogle Scholar
  102. 102.
    Meignin V. Peffault de Latour R. Zuber J, et al. Numbers of Foxp3-expressing CD4+CD25high T cells do not correlate with the establishment of long-term tolerance after allogeneic stem cell transplantation. Exp Hematol. 2005;33:894–900.PubMedGoogle Scholar
  103. 103.
    Hauri-Hohl MM. Keller MP. Gill J, et al. Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation. Blood 2007;109:4080–8.PubMedGoogle Scholar
  104. 104.
    Godfrey WR. Spoden DJ. Ge YG, et al. Cord blood CD4(+)CD25(+)-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function. Blood 2005;105:750–8.PubMedGoogle Scholar
  105. 105.
    Battaglia M. Stabilini A. Migliavacca B. Horejs-Hoeck J. Kaupper T. Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol. 2006;177:8338–47.PubMedGoogle Scholar
  106. 106.
    Godfrey WR. Ge YG. Spoden DJ, et al. In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 2004;104:453–61.PubMedGoogle Scholar
  107. 107.
    Jiang S. Tsang J. Game DS. Stevenson S. Lombardi G. Lechler RI. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: potential reagents to promote donor-specific transplantation tolerance. Transplantation 2006;82:1738–43.PubMedGoogle Scholar
  108. 108.
    Roncarolo MG. Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol. 2007;7:585–98.PubMedGoogle Scholar
  109. 109.
    Zhang H. Chua KS. Guimond M, et al. Lymphopenia and interleukin-2 therapy alter homeostasis of CD4+CD25+ regulatory T cells. Nat Med. 2005;11:1238–43.PubMedGoogle Scholar
  110. 110.
    Mosmann TR. Cherwinski H. Bond MW. Giedlin MA. Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986;136:2348–57.PubMedGoogle Scholar
  111. 111.
    Le Gros G. Ben-Sasson SZ. Seder R. Finkelman FD. Paul WE. Generation of interleukin 4 (IL-4)-producing cells in vivo and in vitro: IL-2 and IL-4 are required for in vitro generation of IL-4-producing cells. J Exp Med. 1990;172:921–9.PubMedGoogle Scholar
  112. 112.
    Yoshimoto T. Bendelac A. Watson C. Hu-Li J. Paul WE. Role of NK1.1+ T cells in a TH2 response and in immunoglobulin E production. Science 1995;270:1845–7.PubMedGoogle Scholar
  113. 113.
    Rodriguez-Palmero M. Hara T. Thumbs A. Hunig T. Triggering of T cell proliferation through CD28 induces GATA-3 and promotes T helper type 2 differentiation in vitro and in vivo. Eur J Immunol. 1999;29:3914–24.PubMedGoogle Scholar
  114. 114.
    Brown DR. Green JM. Moskowitz NH. Davis M. Thompson CB. Reiner SL. Limited role of CD28-mediated signals in T helper subset differentiation. J Exp Med. 1996;184:803–10.PubMedGoogle Scholar
  115. 115.
    Rissoan MC. Soumelis V. Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–6.PubMedGoogle Scholar
  116. 116.
    Kalinski P. Hilkens CM. Snijders A. Snijdewint FG. Kapsenberg ML. IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type 2 cytokine production in maturing human naive T helper cells. J Immunol. 1997;159:28–35.PubMedGoogle Scholar
  117. 117.
    Sallusto F. Lenig D. Forster R. Lipp M. Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999;401:708–12.PubMedGoogle Scholar
  118. 118.
    Kelly BL. Locksley RM. Coordinate regulation of the IL-4, IL-13, and IL-5 cytokine cluster in Th2 clones revealed by allelic expression patterns. J Immunol. 2000;165:2982–6.PubMedGoogle Scholar
  119. 119.
    Croft M. Carter L. Swain SL. Dutton RW. Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin (IL)-4 and IL-12 in promoting type 2 versus type 1 cytokine profiles. J Exp Med. 1994;180:1715–28.PubMedGoogle Scholar
  120. 120.
    Carter LL. Dutton RW. Relative perforin- and Fas-mediated lysis in T1 and T2 CD8 effector populations. J Immunol. 1995;155:1028–31.PubMedGoogle Scholar
  121. 121.
    Peritt D. Robertson S. Gri G. Showe L. Aste-Amezaga M. Trinchieri G. Differentiation of human NK cells into NK1 and NK2 subsets. J Immunol. 1998;161:5821–4.PubMedGoogle Scholar
  122. 122.
    Afkarian M. Sedy JR. Yang J, et al. T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. [comment]. Nat Immunol. 2002;3:549–57.PubMedGoogle Scholar
  123. 123.
    Sallusto F. Lenig D. Mackay CR. Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes. J Exp Med. 1998;187:875–83.PubMedGoogle Scholar
  124. 124.
    Chtanova T. Kemp RA. Sutherland AP. Ronchese F. Mackay CR. Gene microarrays reveal extensive differential gene expression in both CD4(+) and CD8(+) type 1 and type 2 T cells. J Immunol. 2001;167:3057–63.PubMedGoogle Scholar
  125. 125.
    Sher A. Gazzinelli RT. Oswald IP, et al. Role of T-cell derived cytokines in the downregulation of immune responses in parasitic and retroviral infection. Immunol Rev. 1992;127:183–204.PubMedGoogle Scholar
  126. 126.
    Salgame P. Abrams JS. Clayberger C, et al. Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991;254:279–82.PubMedGoogle Scholar
  127. 127.
    Windhagen A. Anderson DE. Carrizosa A. Williams RE. Hafler DA. IL-12 induces human T cells secreting IL-10 with IFN-gamma. J Immunol. 1996;157:1127–31.PubMedGoogle Scholar
  128. 128.
    Cousins DJ. Lee TH. Staynov DZ. Cytokine coexpression during human Th1/Th2 cell differentiation: direct evidence for coordinated expression of Th2 cytokines. J Immunol. 2002;169:2498–506.PubMedGoogle Scholar
  129. 129.
    Via CS. Finkelman FD. Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol. 1993;5:565–72.PubMedGoogle Scholar
  130. 130.
    Blazar BR. Taylor PA. Panoskaltsis-Mortari A, et al. Blockade of CD40 ligand-CD40 interaction impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. J Immunol. 1997;158:29–39.PubMedGoogle Scholar
  131. 131.
    Via CS. Rus V. Gately MK. Finkelman FD. IL-12 stimulates the development of acute graft-versus-host disease in mice that normally would develop chronic, autoimmune graft-versus-host disease. J Immunol. 1994;153:4040–7.PubMedGoogle Scholar
  132. 132.
    Baker MB. Altman NH. Podack ER. Levy RB. The role of cell-mediated cytotoxicity in acute GVHD after MHC-matched allogeneic bone marrow transplantation in mice. J Exp Med. 1996;183:2645–56.PubMedGoogle Scholar
  133. 133.
    Kataoka Y. Iwasaki T. Kuroiwa T, et al. The role of donor T cells for target organ injuries in acute and chronic graft-versus-host disease. Immunology 2001;103:310–8.PubMedGoogle Scholar
  134. 134.
    Nestel FP. Price KS. Seemayer TA. Lapp WS. Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease. J Exp Med. 1992;175:405–13.PubMedGoogle Scholar
  135. 135.
    Abhyankar S. Gilliland DG. Ferrara JL. Interleukin-1 is a critical effector molecule during cytokine dysregulation in graft versus host disease to minor histocompatibility antigens. Transplantation 1993;56:1518–23.PubMedGoogle Scholar
  136. 136.
    Nikolic B. Lee S. Bronson RT. Grusby MJ. Sykes M. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest. 2000;105:1289–98.PubMedGoogle Scholar
  137. 137.
    Liu J. Anderson BE. Robert ME, et al. Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. Blood 2001;98:3367–75.PubMedGoogle Scholar
  138. 138.
    Murphy WJ. Welniak LA. Taub DD, et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest. 1998;102:1742–8.PubMedGoogle Scholar
  139. 139.
    Fowler DH. Kurasawa K. Husebekk A. Cohen PA. Gress RE. Cells of Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. Regulation of cytokines and CD8+ lymphoid engraftment. J Immunol. 1994;152:1004–13.PubMedGoogle Scholar
  140. 140.
    Krenger W. Snyder KM. Byon JC. Falzarano G. Ferrara JL. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol. 1995;155:585–93.PubMedGoogle Scholar
  141. 141.
    Fowler DH. Breglio J. Nagel G. Eckhaus MA. Gress RE. Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol. 1996;157:4811–21.PubMedGoogle Scholar
  142. 142.
    Jung U. Foley JE. Erdmann AA. Eckhaus MA. Fowler DH. CD3/CD28-costimulated T1 and T2 subsets: differential in vivo allosensitization generates distinct GVT and GVHD effects. Blood 2003;102:3439–46.PubMedGoogle Scholar
  143. 143.
    van den Brink MR. Moore E. Ferrara JL. Burakoff SJ. Graft-versus-host-disease-associated thymic damage results in the appearance of T cell clones with anti-host reactivity. Transplantation 2000;69:446–9.PubMedGoogle Scholar
  144. 144.
    Fowler DH. Breglio J. Nagel G. Hirose C. Gress RE. Allospecific CD4+, Th1/Th2 and CD8+, Tc1/Tc2 populations in murine GVL: type I cells generate GVL and type II cells abrogate GVL. Biol Blood Marrow Transplant. 1996;2:118–25.PubMedGoogle Scholar
  145. 145.
    Fowler DH. Shared biology of GVHD and GVT effects: potential methods of separation. Crit Rev Oncol Hematol. 2006;57:225–44.PubMedGoogle Scholar
  146. 146.
    Ramirez-Montagut T. Chow A. Kochman AA, et al. IFN-gamma and Fas ligand are required for graft-versus-tumor activity against renal cell carcinoma in the absence of lethal graft-versus-host disease. J Immunol. 2007;179:1669–80.PubMedGoogle Scholar
  147. 147.
    Dobrzanski MJ. Reome JB. Dutton RW. Therapeutic effects of tumor-reactive type 1 and type 2 CD8+ T cell subpopulations in established pulmonary metastases. J Immunol. 1999;162:6671–80.PubMedGoogle Scholar
  148. 148.
    Foley JE. Jung U. Miera A, et al. Ex vivo rapamycin generates donor Th2 cells that potently inhibit graft-versus-host disease and graft-versus-tumor effects via an IL-4-dependent mechanism. J Immunol. 2005;175:5732–43.PubMedGoogle Scholar
  149. 149.
    Jung U. Foley JE. Erdmann AA, et al. Ex vivo rapamycin generates Th1/Tc1 or Th2/Tc2 Effector T cells with enhanced in vivo function and differential sensitivity to post-transplant rapamycin therapy. Biol Blood Marrow Transplant. 2006;12:905–18.PubMedGoogle Scholar
  150. 150.
    Klebanoff CA. Gattinoni L. Torabi-Parizi P, et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc Natl Acad Sci USA. 2005;102:9571–6.Google Scholar
  151. 151.
    Battaglia M. Stabilini A. Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005;105:4743–8.PubMedGoogle Scholar
  152. 152.
    Teshima T, Matsuo K, Matsue K, et al. Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors. Br J Haematol. 2005;130:575–87.PubMedGoogle Scholar
  153. 153.
    Martin PJ, Akatsuka Y, Hahne M, Sale G. Involvement of donor T-cell cytotoxic effector mechanisms in preventing allogeneic marrow graft rejection. Blood 1998;92:2177–81.PubMedGoogle Scholar
  154. 154.
    Fowler DH, Whitfield B, Livingston M, Chrobak P, Gress RE. Non-host-reactive donor CD8+ T cells of Tc2 phenotype potently inhibit marrow graft rejection. Blood 1998;91:4045–50.PubMedGoogle Scholar
  155. 155.
    Bachar-Lustig E, Reich-Zeliger S, Reisner Y. Anti-third-party veto CTLs overcome rejection of hematopoietic allografts: synergism with rapamycin and BM cell dose. Blood 2003;102:1943–50.PubMedGoogle Scholar
  156. 156.
    Mariotti J, Foley J, Jung U, et al. Ex vivo rapamycin generates apoptosis-resistant donor th2 cells that persist in vivo and prevent hemopoietic stem cell graft rejection. J Immunol. 2008;180:89–105.PubMedGoogle Scholar
  157. 157.
    Fowler DH, Odom J, Steinberg SM, et al. Phase I clinical trial of costimulated, IL-4 polarized donor CD4+ T cells as augmentation of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2006;12:1150–60.PubMedGoogle Scholar
  158. 158.
    Beiting DP, Gagliardo LF, Hesse M, Bliss SK, Meskill D, Appleton JA. Coordinated control of immunity to muscle stage Trichinella spiralis by IL-10, regulatory T cells, and TGF-beta. J Immunol. 2007;178:1039–47.PubMedGoogle Scholar
  159. 159.
    Foley JE, Mariotti J, Amarnath S, Han S, Eckhaus M, Fowler DH. TH2.rapa cell treatment of established murine acute GvHD is abrogated by IL-2 therapy and T regulatory cells. Blood (ASH Annual Meeting Abstracts), 2007;110:2169.Google Scholar
  160. 160.
    Amsen D, Antov A, Jankovic D, et al. Direct regulation of Gata3 expression determines the T helper differentiation potential of Notch. Immunity 2007;27:89–99.PubMedGoogle Scholar
  161. 161.
    Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA. Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines. J Immunol. 1998;160:5355–65.PubMedGoogle Scholar
  162. 162.
    Hackstein H, Taner T, Zahorchak AF, et al. Rapamycin inhibits IL-4-induced dendritic cell maturation in vitro and dendritic cell mobilization and function in vivo. Blood 2003;101:4457–63.PubMedGoogle Scholar
  163. 163.
    Zeiser R, Nguyen VH, Beilhack A, et al. Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production. Blood 2006;108:390–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Experimental Transplantation and Immunology BranchCenter for Cancer Research, National Cancer InstituteBethesdaUSA

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