Helper T-Cell Differentiation in Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation



Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapeutic option for many malignant diseases. However, the efficacy of allo-HSCT is limited by the occurrence of destructive graft-versus-host disease (GVHD). Since allogeneic T cells are the driving force in the development of GVHD, their activation, proliferation, and differentiation are key factors to understanding GVHD pathogenesis. This review focuses on one critical aspect: the differentiation and function of helper T (Th) cells in acute GVHD. We first summarize well-established subsets including Th1, Th2, Th17, and T-regulatory cells; their flexibility, plasticity, and epigenetic modification; and newly identified subsets including Th9, Th22, and T follicular helper cells. Next, we extensively discuss preclinical findings of Th-cell lineages in GVHD: the networks of transcription factors involved in differentiation, the cytokine and signaling requirements for development, the reciprocal differentiation features, and the regulation of microRNAs on T-cell differentiation. Finally, we briefly summarize the recent findings on the roles of T-cell subsets in clinical GVHD and ongoing strategies to modify T-cell differentiation for controlling GVHD in patients. We believe further exploration and understanding of the immunobiology of T-cell differentiation in GVHD will expand therapeutic options for the continuing success of allo-HSCT.


Allo-HSCT GVL GVHD T-cell differentiation 



We thank the current and past members of Dr. Yu’s laboratory for their intellectual input and hard work. The research in Dr. Yu’s laboratory has been supported in part by grants from the National Institutes of Health (R01s CA11816, CA143812, AI 082685, and CA169116).


  1. Abbas AK, Murphy KM et al (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793PubMedGoogle Scholar
  2. Abbas AK, Benoist C et al (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14:307–308PubMedGoogle Scholar
  3. Afkarian M, Sedy JR et al (2002) T-bet is a STAT1-induced regulator of IL-12R expression in naive CD4+ T cells. Nat Immunol 3:549–557PubMedGoogle Scholar
  4. Agarwal S, Rao A (1998) Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9:765–775PubMedGoogle Scholar
  5. Aggarwal S, Ghilardi N et al (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterized by the production of interleukin-17. J Biol Chem 278:1910–1914PubMedGoogle Scholar
  6. Akimzhanov AM, Yang XO et al (2007) Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem 282:5969–5972PubMedGoogle Scholar
  7. Annunziato F, Cosmi L et al (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204:1849–1861PubMedCentralPubMedGoogle Scholar
  8. Antin JH, Ferrara JL (1992) Cytokine dysregulation and acute graft-versus-host disease. Blood 80:2964–2968PubMedGoogle Scholar
  9. Antin JH, Kim HT et al (2003) Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood 102:1601–1605PubMedGoogle Scholar
  10. Appelbaum FR (2001) Haematopoietic cell transplantation as immunotherapy. Nature 411:385–389PubMedGoogle Scholar
  11. Atkins MB, Lotze MT et al (1999) High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol 17:2105–2116PubMedGoogle Scholar
  12. Baltimore D, Boldin MP et al (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845PubMedGoogle Scholar
  13. Banovic T, Macdonald KP et al (2005) TGF-beta in allogeneic stem cell transplantation: friend or foe? Blood 106:2206–2214PubMedGoogle Scholar
  14. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedGoogle Scholar
  15. Battaglia M, Stabilini A et al (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748PubMedGoogle Scholar
  16. Becher B, Durell BG et al (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497PubMedCentralPubMedGoogle Scholar
  17. Bensinger SJ, Bradley MN et al (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111PubMedCentralPubMedGoogle Scholar
  18. Bettelli E, Carrier Y et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238PubMedGoogle Scholar
  19. Bettelli E, Oukka M et al (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350PubMedGoogle Scholar
  20. Betts BC, Abdel-Wahab O et al (2011) Janus kinase-2 inhibition induces durable tolerance to alloantigen by human dendritic cell-stimulated T cells yet preserves immunity to recall antigen. Blood 118:5330–5339PubMedCentralPubMedGoogle Scholar
  21. Blazar BR, Murphy WJ (2005) Bone marrow transplantation and approaches to avoid graft-versus-host disease (GVHD). Philos Trans R Soc Lond B Biol Sci 360:1747–1767PubMedCentralPubMedGoogle Scholar
  22. Blazar BR, Korngold R et al (1997) Recent advances in graft-versus-host disease (GVHD) prevention. Immunol Rev 157:79–109PubMedGoogle Scholar
  23. Blazar BR, Murphy WJ et al (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12:443–458PubMedCentralPubMedGoogle Scholar
  24. Bonnotte B, Burdiles AM et al (1996) Serum interleukin-12 levels in patients undergoing allogeneic or autologous bone marrow transplantation. Eur Cytokine Netw 7:389–394PubMedGoogle Scholar
  25. Brok HP, Heidt PJ et al (1993) Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol 151:6451–6459PubMedGoogle Scholar
  26. Brunstein CG, Miller JS et al (2011) Infusion of ex vivo expanded T regulatory cells in adults transplanted with umbilical cord blood: safety profile and detection kinetics. Blood 117:1061–1070PubMedCentralPubMedGoogle Scholar
  27. Brustle A, Heink S et al (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8:958–966PubMedGoogle Scholar
  28. Bucher C, Koch L et al (2009) IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood 114:5375–5384PubMedCentralPubMedGoogle Scholar
  29. Burman AC, Banovic T et al (2007) IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 110:1064–1072PubMedGoogle Scholar
  30. Carayol G, Bourhis JH et al (1997) Quantitative analysis of T helper 1, T helper 2, and inflammatory cytokine expression in patients after allogeneic bone marrow transplantation: relationship with the occurrence of acute graft-versus-host disease. Transplantation 63:1307–1313PubMedGoogle Scholar
  31. Carlson MJ, West ML et al (2009) In vitro-differentiated TH17 cells mediate lethal acute graft-versus-host disease with severe cutaneous and pulmonary pathologic manifestations. Blood 113:1365–1374PubMedCentralPubMedGoogle Scholar
  32. Carmell MA, Hannon GJ (2004) RNase III enzymes and the initiation of gene silencing. Nat Struct Mol Biol 11:214–218PubMedGoogle Scholar
  33. Cavet J, Dickinson AM et al (2001) Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood 98:1594–1600PubMedGoogle Scholar
  34. Chang HC, Sehra S et al (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11:527–534PubMedCentralPubMedGoogle Scholar
  35. Chen Z, Laurence A et al (2006) Selective regulatory function of Socs3 in the formation of IL-17-secreting T cells. Proc Natl Acad Sci USA 103:8137–8142PubMedCentralPubMedGoogle Scholar
  36. Chen Q, Yang W et al (2008) IRF-4-binding protein inhibits interleukin-17 and interleukin-21 production by controlling the activity of IRF-4 transcription factor. Immunity 29:899–911PubMedCentralPubMedGoogle Scholar
  37. Chen X, Das R et al (2009) Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease. Blood 114:891–900PubMedCentralPubMedGoogle Scholar
  38. Cherwinski HM, Schumacher JH et al (1987) Two types of mouse helper T cell clone. III. Further differences in lymphokine synthesis between Th1 and Th2 clones revealed by RNA hybridization, functionally monospecific bioassays, and monoclonal antibodies. J Exp Med 166:1229–1244PubMedGoogle Scholar
  39. Chong MM, Rasmussen JP et al (2008) The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 205:2005–2017PubMedCentralPubMedGoogle Scholar
  40. Ciofani M, Madar A et al (2012) A validated regulatory network for Th17 cell specification. Cell 151:289–303PubMedCentralPubMedGoogle Scholar
  41. Coghill JM, Sarantopoulos S et al (2011) Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. Blood 117:3268–3276PubMedCentralPubMedGoogle Scholar
  42. Cooke KR, Hill GR et al (1998) Tumor necrosis factor- alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest 102:1882–1891PubMedCentralPubMedGoogle Scholar
  43. Couriel D, Saliba R et al (2004) Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 104:649–654PubMedGoogle Scholar
  44. Couturier M, Lamarthee B et al (2013) IL-22 deficiency in donor T cells attenuates murine acute graft-versus-host disease mortality while sparing the graft-versus-leukemia effect. Leukemia 27:1527–1537PubMedGoogle Scholar
  45. Cretney E, Xin A et al (2011) The transcription factors Blimp-1 and IRF4 jointly control the differentiation and function of effector regulatory T cells. Nat Immunol 12:304–311PubMedGoogle Scholar
  46. Cui G, Qin X et al (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 121:658–670PubMedCentralPubMedGoogle Scholar
  47. Dander E, Balduzzi A et al (2009) Interleukin-17-producing T-helper cells as new potential player mediating graft-versus-host disease in patients undergoing allogeneic stem-cell transplantation. Transplantation 88:1261–1272PubMedGoogle Scholar
  48. Dardalhon V, Awasthi A et al (2008a) IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol 9:1347–1355PubMedCentralPubMedGoogle Scholar
  49. Dardalhon V, Korn T et al (2008b) Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun 31:252–256PubMedCentralPubMedGoogle Scholar
  50. Das R, Chen X et al (2009) Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease. Blood 113:2352–2362PubMedCentralPubMedGoogle Scholar
  51. Das R, Komorowski R et al (2010) Blockade of interleukin-23 signaling results in targeted protection of the colon and allows for separation of graft-versus-host and graft-versus-leukemia responses. Blood 115:5249–5258PubMedCentralPubMedGoogle Scholar
  52. Delgoffe GM, Kole TP et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844PubMedCentralPubMedGoogle Scholar
  53. Djuretic IM, Levanon D et al (2007) Transcription factors T-bet and Runx3 cooperate to activate Ifng and silence Il4 in T helper type 1 cells. Nat Immunol 8:145–153PubMedGoogle Scholar
  54. Drobyski WR, Pasquini M et al (2011) Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transpl 17:1862–1868Google Scholar
  55. Du C, Liu C et al (2009) MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat Immunol 10:1252–1259PubMedGoogle Scholar
  56. Duhen T, Geiger R et al (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat Immunol 10:857–863PubMedGoogle Scholar
  57. Durant L, Watford WT et al (2010) Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32:605–615PubMedCentralPubMedGoogle Scholar
  58. Edinger M, Hoffmann P 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 9:1144–1150PubMedGoogle Scholar
  59. Elyaman W, Bradshaw EM et al (2009) IL-9 induces differentiation of TH17 cells and enhances function of FoxP3+ natural regulatory T cells. Proc Natl Acad Sci USA 106:12885–12890PubMedCentralPubMedGoogle Scholar
  60. Espinoza JL, Takami A et al (2011) A genetic variant in the IL-17 promoter is functionally associated with acute graft-versus-host disease after unrelated bone marrow transplantation. PLoS ONE 6:e26229PubMedCentralPubMedGoogle Scholar
  61. Eyerich S, Eyerich K et al (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. J Clin Invest 119:3573–3585PubMedCentralPubMedGoogle Scholar
  62. Feng T, Cao AT et al (2011) Interleukin-12 converts Foxp3+ regulatory T cells to interferon-gamma-producing Foxp3+ T cells that inhibit colitis. Gastroenterology 140:2031–2043PubMedCentralPubMedGoogle Scholar
  63. Ferrara JL, Krenger W (1998) Graft-versus-host disease: the influence of type 1 and type 2 T cell cytokines. Transfus Med Rev 12:1–17PubMedGoogle Scholar
  64. Ferrara JL, Levine JE et al (2009) Graft-versus-host disease. Lancet 373:1550–1561PubMedCentralPubMedGoogle Scholar
  65. Foley JE, Jung U et al (2005) 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 175:5732–5743PubMedGoogle Scholar
  66. Foley JE, Mariotti J et al (2008) Th2 cell therapy of established acute graft-versus-host disease requires IL-4 and IL-10 and is abrogated by IL-2 or host-type antigen-presenting cells. Biol Blood Marrow Transpl 14:959–972Google Scholar
  67. Fontenot JD, Rasmussen JP et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341PubMedGoogle Scholar
  68. Fossiez F, Djossou O et al (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593–2603PubMedGoogle Scholar
  69. Fowler DH, Gress RE (2000) Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leuk Lymphoma 38:221–234PubMedGoogle Scholar
  70. Fowler DH, Kurasawa K et al (1994) Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood 84:3540–3549PubMedGoogle Scholar
  71. Fulton LM, Carlson MJ et al (2012) Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORgammat. J Immunol 189:1765–1772PubMedCentralPubMedGoogle Scholar
  72. Gergis U, Arnason J et al (2010) Effectiveness and safety of tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, in a patient with refractory GI graft-versus-host disease. J Clin Oncol 28:e602–e604PubMedGoogle Scholar
  73. Gerondakis S, Grumont R et al (2006) Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25:6781–6799PubMedGoogle Scholar
  74. Ghoreschi K, Laurence A et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971PubMedCentralPubMedGoogle Scholar
  75. Ghosh A, Dogan Y et al (2013) Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. J Clin Invest 123:2654–2662PubMedCentralPubMedGoogle Scholar
  76. Glatman Zaretsky A, Taylor JJ et al (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206:991–999PubMedGoogle Scholar
  77. Goker H, Haznedaroglu IC et al (2001) Acute graft-vs-host disease: pathobiology and management. Exp Hematol 29:259–277PubMedGoogle Scholar
  78. Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186:3283–3288PubMedCentralPubMedGoogle Scholar
  79. Greenwood J, Steinman L et al (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6:358–370PubMedGoogle Scholar
  80. Grimbacher B, Hutloff A et al (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268PubMedGoogle Scholar
  81. Grogan JL, Mohrs M et al (2001) Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14:205–215PubMedGoogle Scholar
  82. Hamadani M, Awan FT et al (2008) The impact of HMG-CoA reductase inhibition on the incidence and severity of graft-versus-host disease in patients with acute leukemia undergoing allogeneic transplantation. Blood 111:3901–3902PubMedGoogle Scholar
  83. Hamadani M, Craig MD et al (2011) The evolving role of statins in hematopoietic stem and progenitor cell transplantation. Am J Blood Res 1:57–64PubMedCentralPubMedGoogle Scholar
  84. Hanash AM, Kappel LW et al (2011) Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL. Blood 118:446–455PubMedCentralPubMedGoogle Scholar
  85. Hanash AM, Dudakov JA et al (2012) Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease. Immunity 37:339–350PubMedCentralPubMedGoogle Scholar
  86. Harrington LE, Hatton RD et al (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123–1132PubMedGoogle Scholar
  87. Hashimoto D, Asakura S et al (2005) Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells. J Immunol 174:551–556PubMedGoogle Scholar
  88. Hegazy AN, Peine M et al (2010) Interferons direct Th2 cell reprogramming to generate a stable GATA-3(+)T-bet(+) cell subset with combined Th2 and Th1 cell functions. Immunity 32:116–128PubMedGoogle Scholar
  89. Hess AD (2006) Modulation of graft-versus-host disease: role of regulatory T lymphocytes. Biol Blood Marrow Transpl 12:13–21Google Scholar
  90. Hildebrandt GC, Choi SW et al (2008) The absence of donor-derived IL-13 exacerbates the severity of acute graft-versus-host disease following allogeneic bone marrow transplantation. Pediatr Blood Cancer 50:911–914PubMedGoogle Scholar
  91. Hippen KL, Merkel SC et al (2011) Massive ex vivo expansion of human natural regulatory T cells (T(regs)) with minimal loss of in vivo functional activity. Sci Translational Med 3:83ra41Google Scholar
  92. Hippen KL, Bucher C et al (2012) Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood 119:619–628PubMedCentralPubMedGoogle Scholar
  93. Hirota K, Duarte JH et al (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12:255–263PubMedCentralPubMedGoogle Scholar
  94. Ho IC, Glimcher LH (2002) Transcription: tantalizing times for T cells. Cell 109(Suppl):S109–S120PubMedGoogle Scholar
  95. Hoffmann P, Ermann J et al (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196:389–399PubMedCentralPubMedGoogle Scholar
  96. Horwitz DA, Zheng SG et al (2008) Critical role of IL-2 and TGF-beta in generation, function and stabilization of Foxp3+CD4+ Treg. Eur J Immunol 38:912–915PubMedGoogle Scholar
  97. Iclozan C, Yu Y et al (2010) T helper17 cells are sufficient but not necessary to induce acute graft-versus-host disease. Biol Blood Marrow Transpl 16:170–178Google Scholar
  98. Ivanov Ii, McKenzie BS et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133PubMedGoogle Scholar
  99. Jenner RG, Townsend MJ et al (2009) The transcription factors T-bet and GATA-3 control alternative pathways of T-cell differentiation through a shared set of target genes. Proc Natl Acad Sci USA 106:17876–17881PubMedCentralPubMedGoogle Scholar
  100. Jenq RR, van den Brink MR (2010) Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10:213–221PubMedGoogle Scholar
  101. Jiang S, Li C et al (2011) Molecular dissection of the miR-17-92 cluster’s critical dual roles in promoting Th1 responses and preventing inducible Treg differentiation. Blood 118:5487–5497PubMedCentralPubMedGoogle Scholar
  102. Johnston LJ, Brown J et al (2005) Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transpl 11:47–55Google Scholar
  103. Jordan WJ, Brookes PA et al (2004) IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation. Blood 103:717–724PubMedGoogle Scholar
  104. Josefowicz SZ, Lu LF et al (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564PubMedGoogle Scholar
  105. Jovanovic DV, Di Battista JA et al (1998) IL-17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 160:3513–3521PubMedGoogle Scholar
  106. Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252:104–115PubMedCentralPubMedGoogle Scholar
  107. Kaplan MH, Schindler U et al (1996) Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4:313–319PubMedGoogle Scholar
  108. Kappel LW, Goldberg GL et al (2009) IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 113:945–952PubMedCentralPubMedGoogle Scholar
  109. Kidoya H, Umemura M et al (2005) Fas ligand induces cell-autonomous IL-23 production in dendritic cells, a mechanism for Fas ligand-induced IL-17 production. J Immunol 175:8024–8031PubMedGoogle Scholar
  110. Kim CH, Rott LS et al (2001) Subspecialization of CXCR5+ T cells: B helper activity is focused in a germinal center-localized subset of CXCR5+ T cells. J Exp Med 193:1373–1381PubMedCentralPubMedGoogle Scholar
  111. Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835PubMedGoogle Scholar
  112. Kimura A, Naka T et al (2008) Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci USA 105:9721–9726PubMedCentralPubMedGoogle Scholar
  113. King C, Tangye SG et al (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766PubMedGoogle Scholar
  114. Koch MA, Tucker-Heard G et al (2009) The transcription factor T-bet controls regulatory T cell homeostasis and function during type 1 inflammation. Nat Immunol 10:595–602PubMedCentralPubMedGoogle Scholar
  115. Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383PubMedGoogle Scholar
  116. Komine O, Hayashi K et al (2003) The Runx1 transcription factor inhibits the differentiation of naive CD4+ T cells into the Th2 lineage by repressing GATA3 expression. J Exp Med 198:51–61PubMedCentralPubMedGoogle Scholar
  117. Koreth J, Matsuoka K et al (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365:2055–2066PubMedCentralPubMedGoogle Scholar
  118. Korn T, Bettelli E et al (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487PubMedCentralPubMedGoogle Scholar
  119. Korngold R, Marini JC et al (2003) Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transpl 9:292–303Google Scholar
  120. Krenger W, Snyder KM et al (1995) Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol 155:585–593PubMedGoogle Scholar
  121. Langrish CL, Chen Y et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240PubMedCentralPubMedGoogle Scholar
  122. Laurence A, O’Shea JJ (2007) T(H)-17 differentiation: of mice and men. Nat Immunol 8:903–905PubMedGoogle Scholar
  123. Laurence A, Tato CM et al (2007) Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:371–381PubMedGoogle Scholar
  124. Laurence A, Amarnath S et al (2012) STAT3 transcription factor promotes instability of nTreg cells and limits generation of iTreg cells during acute murine graft-versus-host disease. Immunity 37:209–222PubMedCentralPubMedGoogle Scholar
  125. Lazarevic V, Glimcher LH (2011) T-bet in disease. Nat Immunol 12:597–606PubMedGoogle Scholar
  126. Lazarevic V, Chen X et al (2011) T-bet represses T(H)17 differentiation by preventing Runx1-mediated activation of the gene encoding RORgammat. Nat Immunol 12:96–104PubMedCentralPubMedGoogle Scholar
  127. Lee CG, Homer RJ et al (2001) Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med 194:809–821PubMedCentralPubMedGoogle Scholar
  128. Lee YK, Turner H et al (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30:92–107PubMedCentralPubMedGoogle Scholar
  129. Lee K, Gudapati P et al (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:743–753PubMedCentralPubMedGoogle Scholar
  130. Leng C, Gries M et al (2006) Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1. Exp Hematol 34:776–787PubMedGoogle Scholar
  131. Levine JE (2011) Implications of TNF-alpha in the pathogenesis and management of GVHD. Int J Hematol 93:571–577PubMedCentralPubMedGoogle Scholar
  132. Li QJ, Chau J et al (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–161PubMedGoogle Scholar
  133. Liang SC, Tan XY et al (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271–2279PubMedCentralPubMedGoogle Scholar
  134. Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118PubMedCentralPubMedGoogle Scholar
  135. Lord GM, Rao RM et al (2005) T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106:3432–3439PubMedCentralPubMedGoogle Scholar
  136. Lu Y, Sakamaki S et al (2001) Prevention of lethal acute graft-versus-host disease in mice by oral administration of T helper 1 inhibitor, TAK-603. Blood 97:1123–1130PubMedGoogle Scholar
  137. Lu LF, Lind EF et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002PubMedGoogle Scholar
  138. Lu SX, Alpdogan O et al (2008) STAT-3 and ERK 1/2 phosphorylation are critical for T-cell alloactivation and graft-versus-host disease. Blood 112:5254–5258PubMedCentralPubMedGoogle Scholar
  139. Lu LF, Boldin MP et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929PubMedCentralPubMedGoogle Scholar
  140. Lu Y, Hong S et al (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122:4160–4171PubMedCentralPubMedGoogle Scholar
  141. Luger D, Silver PB et al (2008) Either a Th17 or a Th1 effector response can drive autoimmunity: conditions of disease induction affect dominant effector category. J Exp Med 205:799–810PubMedCentralPubMedGoogle Scholar
  142. Ma F, Xu S et al (2011a) The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-gamma. Nat Immunol 12:861–869PubMedGoogle Scholar
  143. Ma H, Lu C et al (2011b) Absence of Stat1 in donor CD4(+) T cells promotes the expansion of Tregs and reduces graft-versus-host disease in mice. J Clin Invest 121:2554–2569PubMedCentralPubMedGoogle Scholar
  144. Ma HH, Ziegler J et al (2011c) Sequential activation of inflammatory signaling pathways during graft-versus-host disease (GVHD): early role for STAT1 and STAT3. Cell Immunol 268:37–46PubMedCentralPubMedGoogle Scholar
  145. Mak TW, Shahinian A et al (2003) Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses. Nat Immunol 4:765–772PubMedGoogle Scholar
  146. Mangan PR, Harrington LE et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234PubMedGoogle Scholar
  147. Mapara MY, Leng C et al (2006) Expression of chemokines in GVHD target organs is influenced by conditioning and genetic factors and amplified by GVHR. Biol Blood Marrow Transpl 12:623–634Google Scholar
  148. Martin-Orozco N, Chung Y et al (2009) Th17 cells promote pancreatic inflammation but only induce diabetes efficiently in lymphopenic hosts after conversion into Th1 cells. Eur J Immunol 39:216–224PubMedCentralPubMedGoogle Scholar
  149. Mathur AN, Chang HC et al (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901–4907PubMedGoogle Scholar
  150. Matsuoka K, Koreth J et al (2013) Low-dose interleukin-2 therapy restores regulatory T cell homeostasis in patients with chronic graft-versus-host disease. Sci Transl Med 5:179ra43Google Scholar
  151. Mauermann N, Burian J et al (2008) Interferon-gamma regulates idiopathic pneumonia syndrome, a Th17+ CD4+ T-cell-mediated graft-versus-host disease. Am J Respir Crit Care Med 178:379–388PubMedGoogle Scholar
  152. Mausner-Fainberg K, Luboshits G et al (2008) The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+ CD25+ T cells. Atherosclerosis 197:829–839PubMedGoogle Scholar
  153. McGeachy MJ, Chen Y et al (2009) The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo. Nat Immunol 10:314–324PubMedCentralPubMedGoogle Scholar
  154. McKenzie AN, Culpepper JA et al (1993) Interleukin 13, a T-cell-derived cytokine that regulates human monocyte and B-cell function. Proc Natl Acad Sci USA 90:3735–3739PubMedCentralPubMedGoogle Scholar
  155. Miller SA, Huang AC et al (2008) Coordinated but physically separable interaction with H3K27-demethylase and H3K4-methyltransferase activities are required for T-box protein-mediated activation of developmental gene expression. Genes Dev 22:2980–2993PubMedCentralPubMedGoogle Scholar
  156. Miura Y, Thoburn CJ et al (2004) Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 104:2187–2193PubMedGoogle Scholar
  157. Monticelli S, Ansel KM et al (2005) MicroRNA profiling of the murine hematopoietic system. Genome Biol 6:R71PubMedCentralPubMedGoogle Scholar
  158. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173PubMedGoogle Scholar
  159. Mosmann TR, Cherwinski H et al (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMedGoogle Scholar
  160. Muljo SA, Ansel KM et al (2005) Aberrant T cell differentiation in the absence of Dicer. J Exp Med 202:261–269PubMedCentralPubMedGoogle Scholar
  161. Mullen AC, High FA et al (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910PubMedGoogle Scholar
  162. Mullen AC, Hutchins AS et al (2002) Hlx is induced by and genetically interacts with T-bet to promote heritable T(H)1 gene induction. Nat Immunol 3:652–658PubMedGoogle Scholar
  163. Muranski P, Boni A et al (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373PubMedCentralPubMedGoogle Scholar
  164. Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944PubMedGoogle Scholar
  165. Murphy WJ, Welniak LA et al (1998) 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 102:1742–1748PubMedCentralPubMedGoogle Scholar
  166. New JY, Li B et al (2002) T cell infiltration and chemokine expression: relevance to the disease localization in murine graft-versus-host disease. Bone Marrow Transpl 29:979–986Google Scholar
  167. Nikolic B, Lee S et al (2000) Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest 105:1289–1298PubMedCentralPubMedGoogle Scholar
  168. Nishimori H, Maeda Y et al (2012) Synthetic retinoid Am 80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. Blood 119:285–295PubMedGoogle Scholar
  169. Nistala K, Adams S et al (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 107:14751–14756PubMedCentralPubMedGoogle Scholar
  170. Noelle RJ, Nowak EC (2010) Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10:683–687PubMedGoogle Scholar
  171. Nowak EC, Weaver CT et al (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206:1653–1660PubMedCentralPubMedGoogle Scholar
  172. Nurieva RI, Chung Y et al (2008) Generation of T follicular helper cells is mediated by interleukin-21 but independent of T helper 1, 2, or 17 cell lineages. Immunity 29:138–149PubMedCentralPubMedGoogle Scholar
  173. Oestreich KJ, Huang AC et al (2011) The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J Exp Med 208:1001–1013PubMedCentralPubMedGoogle Scholar
  174. O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283PubMedGoogle Scholar
  175. Oldenhove G, Bouladoux N et al (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31:772–786PubMedCentralPubMedGoogle Scholar
  176. Oppmann B, Lesley R et al (2000) Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13:715–725PubMedGoogle Scholar
  177. Ouyang W, Kolls JK et al (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467PubMedCentralPubMedGoogle Scholar
  178. Ouyang W, Rutz S et al (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109PubMedGoogle Scholar
  179. Pai SY, Truitt ML et al (2004) GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci USA 101:1993–1998PubMedCentralPubMedGoogle Scholar
  180. Pan L, Delmonte J Jr et al (1995) Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood 86:4422–4429PubMedGoogle Scholar
  181. Park H, Li Z et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141PubMedCentralPubMedGoogle Scholar
  182. Parrish-Novak J, Dillon SR et al (2000) Interleukin 21 and its receptor are involved in NK cell expansion and regulation of lymphocyte function. Nature 408:57–63PubMedGoogle Scholar
  183. Peter C, Waldmann H et al (2010) mTOR signalling and metabolic regulation of T cell differentiation. Curr Opin Immunol 22:655–661PubMedGoogle Scholar
  184. Pidala J, Anasetti C (2010) Can antigen-specific regulatory T cells protect against graft versus host disease and spare anti-malignancy alloresponse? Haematologica 95:660–665PubMedCentralPubMedGoogle Scholar
  185. Pidala J, Kim J et al (2009) Sirolimus as primary treatment of acute graft-versus-host disease following allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transpl 15:881–885Google Scholar
  186. Pidala J, Perez L et al (2012) Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transpl 47:747–748Google Scholar
  187. Radojcic V, Pletneva MA et al (2010) STAT3 signaling in CD4+ T cells is critical for the pathogenesis of chronic sclerodermatous graft-versus-host disease in a murine model. J Immunol 184:764–774PubMedCentralPubMedGoogle Scholar
  188. Ranganathan P, Heaphy CE et al (2012) Regulation of acute graft-versus-host disease by microRNA-155. Blood 119:4786–4797PubMedCentralPubMedGoogle Scholar
  189. Ratajczak P, Janin A et al (2010) Th17/Treg ratio in human graft-versus-host disease. Blood 116:1165–1171PubMedCentralPubMedGoogle Scholar
  190. Reddy P, Negrin R et al (2008) Mouse models of bone marrow transplantation. Biol Blood Marrow Transpl 14:129–135Google Scholar
  191. Rigby SM, Rouse T et al (2003) Total lymphoid irradiation nonmyeloablative preconditioning enriches for IL-4-producing CD4+ -TNK cells and skews differentiation of immunocompetent donor CD4+ cells. Blood 101:2024–2032PubMedGoogle Scholar
  192. Ritchie D, Seconi J et al (2005) Prospective monitoring of tumor necrosis factor alpha and interferon gamma to predict the onset of acute and chronic graft-versus-host disease after allogeneic stem cell transplantation. Biol Blood Marrow Transpl 11:706–712Google Scholar
  193. Robb RJ, Hill GR (2012) The interferon-dependent orchestration of innate and adaptive immunity after transplantation. Blood 119:5351–5358PubMedGoogle Scholar
  194. Rohlman D, Punj S et al (2013) Suppression of acute graft-versus-host response by TCDD is independent of the CTLA-4-IFN-gamma-IDO pathway. Toxicol Sci 135:81–90PubMedGoogle Scholar
  195. Romagnani S (1992) Type 1 T helper and type 2 T helper cells: functions, regulation and role in protection and disease. Int J Clin Lab Res 21:152–158Google Scholar
  196. Rouvier E, Luciani MF et al (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol 150:5445–5456PubMedGoogle Scholar
  197. Roy J, Blazar BR et al (1995) The tissue expression of cytokines in human acute cutaneous graft-versus-host disease. Transplantation 60:343–348PubMedGoogle Scholar
  198. Rubtsov YP, Niec RE et al (2010) Stability of the regulatory T cell lineage in vivo. Science 329:1667–1671PubMedGoogle Scholar
  199. Saadoun D, Rosenzwajg M et al (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077PubMedGoogle Scholar
  200. Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352PubMedGoogle Scholar
  201. Sakaguchi S, Sakaguchi N et al (2001) Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18–32PubMedGoogle Scholar
  202. Sakaguchi S, Vignali DA et al (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13:461–467PubMedGoogle Scholar
  203. Samoilova EB, Horton JL et al (1998) IL-6-deficient mice are resistant to experimental autoimmune encephalomyelitis: roles of IL-6 in the activation and differentiation of autoreactive T cells. J Immunol 161:6480–6486PubMedGoogle Scholar
  204. Schaerli P, Willimann K et al (2000) CXC chemokine receptor 5 expression defines follicular homing T cells with B cell helper function. J Exp Med 192:1553–1562PubMedCentralPubMedGoogle Scholar
  205. Schindler C, Plumlee C (2008) Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol 19:311–318PubMedCentralPubMedGoogle Scholar
  206. Schoenborn JR, Dorschner MO et al (2007) Comprehensive epigenetic profiling identifies multiple distal regulatory elements directing transcription of the gene encoding interferon-gamma. Nat Immunol 8:732–742PubMedCentralPubMedGoogle Scholar
  207. Semple K, Yu Y et al (2011) Efficient and selective prevention of GVHD by antigen-specific induced Tregs via linked-suppression in mice. Biol Blood Marrow Transpl 17:309–318Google Scholar
  208. Shi G, Cox CA et al (2008) Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J Immunol 181:7205–7213PubMedCentralPubMedGoogle Scholar
  209. Shimoda K, Van Deursen J et al (1996) Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature 380:630–633PubMedGoogle Scholar
  210. Shin HJ, Baker J 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 118:2342–2350PubMedGoogle Scholar
  211. Shlomchik WD (2007) Graft-versus-host disease. Nat Rev Immunol 7:340–352PubMedGoogle Scholar
  212. Socie G, Blazar BR (2009) Acute graft-versus-host disease: from the bench to the bedside. Blood 114:4327–4336PubMedCentralPubMedGoogle Scholar
  213. Soligo M, Camperio C et al (2011) CD28 costimulation regulates FOXP3 in a RelA/NF-kappaB-dependent mechanism. Eur J Immunol 41:503–513PubMedGoogle Scholar
  214. Soroosh P, Doherty TA (2009) Th9 and allergic disease. Immunology 127:450–458PubMedCentralPubMedGoogle Scholar
  215. Staudt V, Bothur E et al (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33:192–202PubMedGoogle Scholar
  216. Steiner DF, Thomas MF et al (2011) MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity 35:169–181PubMedCentralPubMedGoogle Scholar
  217. Stephens GL, Swerdlow B et al (2011) IL-9 is a Th17-derived cytokine that limits pathogenic activity in organ-specific autoimmune disease. Eur J Immunol 41:952–962PubMedGoogle Scholar
  218. Stittrich AB, Haftmann C et al (2010) The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat Immunol 11:1057–1062PubMedGoogle Scholar
  219. Stritesky GL, Muthukrishnan R et al (2011) The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34:39–49PubMedCentralPubMedGoogle Scholar
  220. Sun Y, Varambally S et al (2011) Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood 117:6172–6183PubMedCentralPubMedGoogle Scholar
  221. Sun K, Hsiao HH et al (2012) IFN-gamma receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation. J Immunol 189:2033–2042PubMedCentralPubMedGoogle Scholar
  222. Sun Y, Sun J et al (2013) PU.1-dependent transcriptional regulation of miR-142 contributes to its hematopoietic cell-specific expression and modulation of IL-6. J Immunol 190:4005–4013PubMedCentralPubMedGoogle Scholar
  223. Sutton C, Brereton C et al (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203:1685–1691PubMedCentralPubMedGoogle Scholar
  224. Sykes M, Harty MW et al (1994) Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. Blood 83:2560–2569PubMedGoogle Scholar
  225. Szabo SJ, Kim ST et al (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669PubMedGoogle Scholar
  226. Takeda K, Tanaka T et al (1996) Essential role of Stat6 in IL-4 signalling. Nature 380:627–630PubMedGoogle Scholar
  227. Takemoto N, Kamogawa Y et al (2000) Cutting edge: chromatin remodeling at the IL-4/IL-13 intergenic regulatory region for Th2-specific cytokine gene cluster. J Immunol 165:6687–6691PubMedGoogle Scholar
  228. Tanaka J, Imamura M et al (1993) Cytokine gene expression in peripheral blood mononuclear cells during graft-versus-host disease after allogeneic bone marrow transplantation. Br J Haematol 85:558–565PubMedGoogle Scholar
  229. Tato CM, O’Shea JJ (2006) Immunology: what does it mean to be just 17? Nature 441:166–168PubMedGoogle Scholar
  230. Tawara I, Maeda Y et al (2008) Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease. Exp Hematol 36:988–996PubMedCentralPubMedGoogle Scholar
  231. Tawara I, Koyama M et al (2011) Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res 17:77–88PubMedCentralPubMedGoogle Scholar
  232. Taylor PA, Lees CJ et al (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499PubMedGoogle Scholar
  233. Thierfelder WE, Van Deursen JM et al (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174PubMedGoogle Scholar
  234. Thieu VT, Yu Q et al (2008) Signal transducer and activator of transcription 4 is required for the transcription factor T-bet to promote T helper 1 cell-fate determination. Immunity 29:679–690PubMedCentralPubMedGoogle Scholar
  235. Tian T, Yu S et al (2013) Th22 and related cytokines in inflammatory and autoimmune diseases. Expert Opin Ther Targets 17:113–125PubMedGoogle Scholar
  236. Tresoldi E, Dell’albani I et al (2011) Stability of human rapamycin-expanded CD4+ CD25+ T regulatory cells. Haematologica 96:1357–1365PubMedCentralPubMedGoogle Scholar
  237. Tsuji M, Komatsu N et al (2009) Preferential generation of follicular B helper T cells from Foxp3+ T cells in gut Peyer’s patches. Science 323:1488–1492PubMedGoogle Scholar
  238. Usui T, Nishikomori R et al (2003) GATA-3 suppresses Th1 development by downregulation of Stat4 and not through effects on IL-12Rbeta2 chain or T-bet. Immunity 18:415–428PubMedGoogle Scholar
  239. Veerapathran A, Pidala J et al (2013) Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease. Blood 122:225–261Google Scholar
  240. Veldhoen M, Hocking RJ et al (2006) TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189PubMedGoogle Scholar
  241. Veldhoen M, Hirota K et al (2008a) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109PubMedGoogle Scholar
  242. Veldhoen M, Uyttenhove C et al (2008b) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9:1341–1346PubMedGoogle Scholar
  243. Vincent K, Roy DC et al (2011) Next-generation leukemia immunotherapy. Blood 118:2951–2959PubMedGoogle Scholar
  244. Vink A, Warnier G et al (1999) Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population. J Exp Med 189:1413–1423PubMedCentralPubMedGoogle Scholar
  245. Vogtenhuber C, Bucher C et al (2010) Constitutively active Stat5b in CD4+ T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses. Blood 116:466–474PubMedCentralPubMedGoogle Scholar
  246. Wang YH, Voo KS et al (2010) A novel subset of CD4(+) T(H)2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. J Exp Med 207:2479–2491PubMedCentralPubMedGoogle Scholar
  247. Wei L, Laurence A et al (2007) IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282:34605–34610PubMedCentralPubMedGoogle Scholar
  248. Wei G, Wei L et al (2009) Global mapping of H3K4me3 and H3K27me3 reveals specificity and plasticity in lineage fate determination of differentiating CD4+ T cells. Immunity 30:155–167PubMedCentralPubMedGoogle Scholar
  249. Welniak LA, Blazar BR et al (2000) Opposing roles of interferon-gamma on CD4+ T cell-mediated graft-versus-host disease: effects of conditioning. Biol Blood Marrow Transpl 6:604–612Google Scholar
  250. Welniak LA, Blazar BR et al (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139–170PubMedGoogle Scholar
  251. Wenger NK, Lewis SJ et al (2007) Outcomes of using high- or low-dose atorvastatin in patients 65 years of age or older with stable coronary heart disease. Ann Intern Med 147:1–9PubMedGoogle Scholar
  252. Williamson E, Garside P et al (1997) Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol 159:1208–1215PubMedGoogle Scholar
  253. Wilson CB, Rowell E et al (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9:91–105PubMedGoogle Scholar
  254. Wu B, Huang C et al (2008) IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126:202–210PubMedGoogle Scholar
  255. Wurster AL, Rodgers VL et al (2002) Interleukin 21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naive Th cells into interferon gamma-producing Th1 cells. J Exp Med 196:969–977PubMedCentralPubMedGoogle Scholar
  256. Xiao X, Balasubramanian S et al (2012) OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol 13:981–990PubMedCentralPubMedGoogle Scholar
  257. Xu L, Kitani A et al (2007) Cutting edge: regulatory T cells induce CD4+ CD25-Foxp3- T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta. J Immunol 178:6725–6729PubMedGoogle Scholar
  258. Yang YG, Qi J et al (2002) Donor-derived interferon gamma separates graft-versus-leukemia effects and graft-versus-host disease induced by donor CD8 T cells. Blood 99:4207–4215PubMedGoogle Scholar
  259. Yang XO, Panopoulos AD et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363PubMedGoogle Scholar
  260. Yang L, Anderson DE et al (2008a) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352PubMedCentralPubMedGoogle Scholar
  261. Yang XO, Nurieva R et al (2008b) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56PubMedCentralPubMedGoogle Scholar
  262. Yang XO, Pappu BP et al (2008c) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29–39PubMedCentralPubMedGoogle Scholar
  263. Yang XP, Ghoreschi K et al (2011) Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat Immunol 12:247–254PubMedCentralPubMedGoogle Scholar
  264. Yao Z, Fanslow WC et al (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811–821PubMedGoogle Scholar
  265. Yi T, Zhao D et al (2008) Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 112:2101–2110PubMedCentralPubMedGoogle Scholar
  266. Yi T, Chen Y et al (2009) Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2, and Th17 cells in graft-versus-host disease. Blood 114:3101–3112PubMedCentralPubMedGoogle Scholar
  267. Yu D, Rao S et al (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31:457–468PubMedGoogle Scholar
  268. Yu Y, Wang D et al (2011) Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 118:5011–5020PubMedCentralPubMedGoogle Scholar
  269. Yu Y, Wang D et al (2013) c-Rel is an essential transcription factor for the development of acute graft-versus-host disease in mice. Eur J Immunol 43:2327–2337PubMedGoogle Scholar
  270. Zeiser R, Youssef S et al (2007) Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity. Blood 110:4588–4598PubMedCentralPubMedGoogle Scholar
  271. Zhang N, Pan HF et al (2011) Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 353:41–46PubMedGoogle Scholar
  272. Zhao XY, Xu LL et al (2011) IL-17-producing T cells contribute to acute graft-versus-host disease in patients undergoing unmanipulated blood and marrow transplantation. Eur J Immunol 41:514–526PubMedGoogle Scholar
  273. Zhao K, Zhao D et al (2013) The identification and characteristics of IL-22-producing T cells in acute graft-versus-host disease following allogeneic bone marrow transplantation. Immunobiology 218:1505–1513PubMedGoogle Scholar
  274. Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596PubMedGoogle Scholar
  275. Zheng Y, Chaudhry A et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356PubMedCentralPubMedGoogle Scholar
  276. Zhou L, Ii Ivanov et al (2007) IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967–974PubMedGoogle Scholar
  277. Zhou L, Lopes JE et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240PubMedCentralPubMedGoogle Scholar
  278. Zhu J, Guo L et al (2001) Stat6 is necessary and sufficient for IL-4’s role in Th2 differentiation and cell expansion. J Immunol 166:7276–7281PubMedGoogle Scholar
  279. Zhu J, Cote-Sierra J et al (2003) Stat5 activation plays a critical role in Th2 differentiation. Immunity 19:739–748PubMedGoogle Scholar
  280. Zhu J, Min B et al (2004) Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol 5:1157–1165PubMedGoogle Scholar
  281. Zhu J, Yamane H et al (2006) GATA-3 promotes Th2 responses through three different mechanisms: induction of Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res 16:3–10PubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2014

Authors and Affiliations

  • Jianing Fu
    • 1
    • 3
  • Jessica Heinrichs
    • 2
    • 3
  • Xue-Zhong Yu
    • 3
    • 4
  1. 1.Cancer Biology PhD Program, H. Lee Moffitt Cancer Center and Research InstituteUniversity of South FloridaTampaUSA
  2. 2.Department of Pathology and Cell BiologyUniversity of South FloridaTampaUSA
  3. 3.Department of Microbiology and ImmunologyMedical University of South CarolinaCharlestonUSA
  4. 4.Department of MedicineMedical University of South CarolinaCharlestonUSA

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