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

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Hematopoietic Stem Cell Transplantation

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References

  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.

    PubMed  CAS  Google Scholar 

  2. Bluestone JA. Abbas AK. Natural versus adaptive regulatory T cells. Nat Rev Immunol. 2003;3:253–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  10. Wan YY. Flavell RA. Regulatory T-cell functions are subverted and converted owing to attenuated Foxp3 expression. Nature 2007;445:766–70.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  12. Wing K. Suri-Payer E. Rudin A. CD4+CD25+ -regulatory T cells from mouse to man. Scand J Immunol. 2005;62:1–15.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  19. Thornton AM. Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol. 2000;164:183–90.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  30. Zhao DM. Thornton AM. DiPaolo RJ. Shevach EM. Activated CD4+CD25+ T cells selectively kill B lymphocytes. Blood 2006;107:3925–32.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  33. von Boehmer H. Mechanisms of suppression by suppressor T cells. Nat Immunol. 2005;6:338–44.

    Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  42. Rudensky AY. Campbell DJ. In vivo sites and cellular mechanisms of T reg cell-mediated suppression. J Exp Med. 2006;203:489–92.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  53. Floess S. Freyer J. Siewert C, et al. Epigenetic control of the foxp3 locus in regulatory T cells. PLoS Biol. 2007;5:e38.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  65. Stockinger B. Veldhoen M. Differentiation and function of Th17 T cells. Curr Opin Immunol. 2007;19:281–6.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  68. Bettelli E. Korn T. Kuchroo VK. Th17: the third member of the effector T cell trilogy. Curr Opin Immunol. 2007;19:652–7.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  84. Mottet C. Uhlig HH. Powrie F. Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol. 2003;170:3939–43.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  115. Rissoan MC. Soumelis V. Kadowaki N, et al. Reciprocal control of T helper cell and dendritic cell differentiation. Science 1999;283:1183–6.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  120. Carter LL. Dutton RW. Relative perforin- and Fas-mediated lysis in T1 and T2 CD8 effector populations. J Immunol. 1995;155:1028–31.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  145. Fowler DH. Shared biology of GVHD and GVT effects: potential methods of separation. Crit Rev Oncol Hematol. 2006;57:225–44.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. Battaglia M. Stabilini A. Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005;105:4743–8.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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. 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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

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Fowler, D., Hoffmann, P., Edinger, M. (2009). Functionally Defined T Cell Subsets in Transplantation Biology and Therapy: Regulatory T Cells and Th2 Cells. In: Bishop, M. (eds) Hematopoietic Stem Cell Transplantation. Cancer Treatment and Research, vol 144. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-78580-6_7

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