Skip to main content

Advertisement

SpringerLink
Log in

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

  • Review
  • Published:
Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abbas AK, Murphy KM et al (1996) Functional diversity of helper T lymphocytes. Nature 383:787–793

    CAS  PubMed  Google Scholar 

  • Abbas AK, Benoist C et al (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14:307–308

    CAS  PubMed  Google Scholar 

  • 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 3:549–557

    CAS  PubMed  Google Scholar 

  • Agarwal S, Rao A (1998) Modulation of chromatin structure regulates cytokine gene expression during T cell differentiation. Immunity 9:765–775

    CAS  PubMed  Google Scholar 

  • 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 278:1910–1914

    CAS  PubMed  Google Scholar 

  • 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 282:5969–5972

    CAS  PubMed  Google Scholar 

  • Annunziato F, Cosmi L et al (2007) Phenotypic and functional features of human Th17 cells. J Exp Med 204:1849–1861

    CAS  PubMed Central  PubMed  Google Scholar 

  • Antin JH, Ferrara JL (1992) Cytokine dysregulation and acute graft-versus-host disease. Blood 80:2964–2968

    CAS  PubMed  Google Scholar 

  • 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 102:1601–1605

    CAS  PubMed  Google Scholar 

  • Appelbaum FR (2001) Haematopoietic cell transplantation as immunotherapy. Nature 411:385–389

    CAS  PubMed  Google Scholar 

  • 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 17:2105–2116

    CAS  PubMed  Google Scholar 

  • Baltimore D, Boldin MP et al (2008) MicroRNAs: new regulators of immune cell development and function. Nat Immunol 9:839–845

    CAS  PubMed  Google Scholar 

  • Banovic T, Macdonald KP et al (2005) TGF-beta in allogeneic stem cell transplantation: friend or foe? Blood 106:2206–2214

    CAS  PubMed  Google Scholar 

  • Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    CAS  PubMed  Google Scholar 

  • Battaglia M, Stabilini A et al (2005) Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 105:4743–4748

    CAS  PubMed  Google Scholar 

  • Becher B, Durell BG et al (2002) Experimental autoimmune encephalitis and inflammation in the absence of interleukin-12. J Clin Invest 110:493–497

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bensinger SJ, Bradley MN et al (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bettelli E, Carrier Y et al (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    CAS  PubMed  Google Scholar 

  • Bettelli E, Oukka M et al (2007) T(H)-17 cells in the circle of immunity and autoimmunity. Nat Immunol 8:345–350

    CAS  PubMed  Google Scholar 

  • 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 118:5330–5339

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 360:1747–1767

    CAS  PubMed Central  PubMed  Google Scholar 

  • Blazar BR, Korngold R et al (1997) Recent advances in graft-versus-host disease (GVHD) prevention. Immunol Rev 157:79–109

    CAS  PubMed  Google Scholar 

  • Blazar BR, Murphy WJ et al (2012) Advances in graft-versus-host disease biology and therapy. Nat Rev Immunol 12:443–458

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bonnotte B, Burdiles AM et al (1996) Serum interleukin-12 levels in patients undergoing allogeneic or autologous bone marrow transplantation. Eur Cytokine Netw 7:389–394

    CAS  PubMed  Google Scholar 

  • Brok HP, Heidt PJ et al (1993) Interferon-gamma prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol 151:6451–6459

    CAS  PubMed  Google Scholar 

  • 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 117:1061–1070

    CAS  PubMed Central  PubMed  Google Scholar 

  • Brustle A, Heink S et al (2007) The development of inflammatory T(H)-17 cells requires interferon-regulatory factor 4. Nat Immunol 8:958–966

    PubMed  Google Scholar 

  • Bucher C, Koch L et al (2009) IL-21 blockade reduces graft-versus-host disease mortality by supporting inducible T regulatory cell generation. Blood 114:5375–5384

    CAS  PubMed Central  PubMed  Google Scholar 

  • Burman AC, Banovic T et al (2007) IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract. Blood 110:1064–1072

    CAS  PubMed  Google Scholar 

  • 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 63:1307–1313

    CAS  PubMed  Google Scholar 

  • 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 113:1365–1374

    CAS  PubMed Central  PubMed  Google Scholar 

  • Carmell MA, Hannon GJ (2004) RNase III enzymes and the initiation of gene silencing. Nat Struct Mol Biol 11:214–218

    CAS  PubMed  Google Scholar 

  • 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 98:1594–1600

    CAS  PubMed  Google Scholar 

  • 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 11:527–534

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 103:8137–8142

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 29:899–911

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 114:891–900

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 166:1229–1244

    CAS  PubMed  Google Scholar 

  • Chong MM, Rasmussen JP et al (2008) The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J Exp Med 205:2005–2017

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ciofani M, Madar A et al (2012) A validated regulatory network for Th17 cell specification. Cell 151:289–303

    CAS  PubMed Central  PubMed  Google Scholar 

  • Coghill JM, Sarantopoulos S et al (2011) Effector CD4+ T cells, the cytokines they generate, and GVHD: something old and something new. Blood 117:3268–3276

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 102:1882–1891

    CAS  PubMed Central  PubMed  Google Scholar 

  • Couriel D, Saliba R et al (2004) Tumor necrosis factor-alpha blockade for the treatment of acute GVHD. Blood 104:649–654

    CAS  PubMed  Google Scholar 

  • 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 27:1527–1537

    CAS  PubMed  Google Scholar 

  • 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 12:304–311

    CAS  PubMed  Google Scholar 

  • Cui G, Qin X et al (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 121:658–670

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 88:1261–1272

    CAS  PubMed  Google Scholar 

  • 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 9:1347–1355

    CAS  PubMed Central  PubMed  Google Scholar 

  • Dardalhon V, Korn T et al (2008b) Role of Th1 and Th17 cells in organ-specific autoimmunity. J Autoimmun 31:252–256

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 113:2352–2362

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 115:5249–5258

    CAS  PubMed Central  PubMed  Google Scholar 

  • Delgoffe GM, Kole TP et al (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 8:145–153

    CAS  PubMed  Google Scholar 

  • Drobyski WR, Pasquini M et al (2011) Tocilizumab for the treatment of steroid refractory graft-versus-host disease. Biol Blood Marrow Transpl 17:1862–1868

    CAS  Google Scholar 

  • 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 10:1252–1259

    CAS  PubMed  Google Scholar 

  • 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 10:857–863

    CAS  PubMed  Google Scholar 

  • Durant L, Watford WT et al (2010) Diverse targets of the transcription factor STAT3 contribute to T cell pathogenicity and homeostasis. Immunity 32:605–615

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 9:1144–1150

    CAS  PubMed  Google Scholar 

  • 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 106:12885–12890

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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:e26229

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 119:3573–3585

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 140:2031–2043

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ferrara JL, Krenger W (1998) Graft-versus-host disease: the influence of type 1 and type 2 T cell cytokines. Transfus Med Rev 12:1–17

    CAS  PubMed  Google Scholar 

  • Ferrara JL, Levine JE et al (2009) Graft-versus-host disease. Lancet 373:1550–1561

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 175:5732–5743

    CAS  PubMed  Google Scholar 

  • 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 14:959–972

    CAS  Google Scholar 

  • Fontenot JD, Rasmussen JP et al (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22:329–341

    CAS  PubMed  Google Scholar 

  • Fossiez F, Djossou O et al (1996) T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines. J Exp Med 183:2593–2603

    CAS  PubMed  Google Scholar 

  • 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 38:221–234

    CAS  PubMed  Google Scholar 

  • 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 84:3540–3549

    CAS  PubMed  Google Scholar 

  • Fulton LM, Carlson MJ et al (2012) Attenuation of acute graft-versus-host disease in the absence of the transcription factor RORgammat. J Immunol 189:1765–1772

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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–e604

    CAS  PubMed  Google Scholar 

  • Gerondakis S, Grumont R et al (2006) Unravelling the complexities of the NF-kappaB signalling pathway using mouse knockout and transgenic models. Oncogene 25:6781–6799

    CAS  PubMed  Google Scholar 

  • Ghoreschi K, Laurence A et al (2010) Generation of pathogenic T(H)17 cells in the absence of TGF-beta signalling. Nature 467:967–971

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ghosh A, Dogan Y et al (2013) Adoptively transferred TRAIL+ T cells suppress GVHD and augment antitumor activity. J Clin Invest 123:2654–2662

    CAS  PubMed Central  PubMed  Google Scholar 

  • Glatman Zaretsky A, Taylor JJ et al (2009) T follicular helper cells differentiate from Th2 cells in response to helminth antigens. J Exp Med 206:991–999

    PubMed  Google Scholar 

  • Goker H, Haznedaroglu IC et al (2001) Acute graft-vs-host disease: pathobiology and management. Exp Hematol 29:259–277

    CAS  PubMed  Google Scholar 

  • Goswami R, Kaplan MH (2011) A brief history of IL-9. J Immunol 186:3283–3288

    CAS  PubMed Central  PubMed  Google Scholar 

  • Greenwood J, Steinman L et al (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6:358–370

    CAS  PubMed  Google Scholar 

  • Grimbacher B, Hutloff A et al (2003) Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol 4:261–268

    CAS  PubMed  Google Scholar 

  • Grogan JL, Mohrs M et al (2001) Early transcription and silencing of cytokine genes underlie polarization of T helper cell subsets. Immunity 14:205–215

    CAS  PubMed  Google Scholar 

  • 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 111:3901–3902

    CAS  PubMed  Google Scholar 

  • Hamadani M, Craig MD et al (2011) The evolving role of statins in hematopoietic stem and progenitor cell transplantation. Am J Blood Res 1:57–64

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 118:446–455

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 37:339–350

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 6:1123–1132

    CAS  PubMed  Google Scholar 

  • 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 174:551–556

    CAS  PubMed  Google Scholar 

  • 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 32:116–128

    CAS  PubMed  Google Scholar 

  • Hess AD (2006) Modulation of graft-versus-host disease: role of regulatory T lymphocytes. Biol Blood Marrow Transpl 12:13–21

    Google Scholar 

  • 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 50:911–914

    PubMed  Google Scholar 

  • 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 3:83ra41

    Google Scholar 

  • Hippen KL, Bucher C et al (2012) Blocking IL-21 signaling ameliorates xenogeneic GVHD induced by human lymphocytes. Blood 119:619–628

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hirota K, Duarte JH et al (2011) Fate mapping of IL-17-producing T cells in inflammatory responses. Nat Immunol 12:255–263

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ho IC, Glimcher LH (2002) Transcription: tantalizing times for T cells. Cell 109(Suppl):S109–S120

    CAS  PubMed  Google Scholar 

  • 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 196:389–399

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 38:912–915

    CAS  PubMed  Google Scholar 

  • 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 16:170–178

    CAS  Google Scholar 

  • Ivanov Ii, McKenzie BS et al (2006) The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126:1121–1133

    CAS  PubMed  Google Scholar 

  • 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 106:17876–17881

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jenq RR, van den Brink MR (2010) Allogeneic haematopoietic stem cell transplantation: individualized stem cell and immune therapy of cancer. Nat Rev Cancer 10:213–221

    CAS  PubMed  Google Scholar 

  • 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 118:5487–5497

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johnston LJ, Brown J et al (2005) Rapamycin (sirolimus) for treatment of chronic graft-versus-host disease. Biol Blood Marrow Transpl 11:47–55

    CAS  Google Scholar 

  • 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 103:717–724

    CAS  PubMed  Google Scholar 

  • Josefowicz SZ, Lu LF et al (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564

    CAS  PubMed  Google Scholar 

  • 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 160:3513–3521

    CAS  PubMed  Google Scholar 

  • Kaplan MH (2013) Th9 cells: differentiation and disease. Immunol Rev 252:104–115

    PubMed Central  PubMed  Google Scholar 

  • Kaplan MH, Schindler U et al (1996) Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity 4:313–319

    CAS  PubMed  Google Scholar 

  • Kappel LW, Goldberg GL et al (2009) IL-17 contributes to CD4-mediated graft-versus-host disease. Blood 113:945–952

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 175:8024–8031

    CAS  PubMed  Google Scholar 

  • 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 193:1373–1381

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kimura A, Kishimoto T (2010) IL-6: regulator of Treg/Th17 balance. Eur J Immunol 40:1830–1835

    CAS  PubMed  Google Scholar 

  • 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 105:9721–9726

    CAS  PubMed Central  PubMed  Google Scholar 

  • King C, Tangye SG et al (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766

    CAS  PubMed  Google Scholar 

  • 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 10:595–602

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kolb HJ (2008) Graft-versus-leukemia effects of transplantation and donor lymphocytes. Blood 112:4371–4383

    CAS  PubMed  Google Scholar 

  • 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 198:51–61

    CAS  PubMed Central  PubMed  Google Scholar 

  • Koreth J, Matsuoka K et al (2011) Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 365:2055–2066

    CAS  PubMed Central  PubMed  Google Scholar 

  • Korn T, Bettelli E et al (2007) IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 448:484–487

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 9:292–303

    CAS  Google Scholar 

  • 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 155:585–593

    CAS  PubMed  Google Scholar 

  • Langrish CL, Chen Y et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    CAS  PubMed Central  PubMed  Google Scholar 

  • Laurence A, O’Shea JJ (2007) T(H)-17 differentiation: of mice and men. Nat Immunol 8:903–905

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • 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 37:209–222

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lazarevic V, Glimcher LH (2011) T-bet in disease. Nat Immunol 12:597–606

    CAS  PubMed  Google Scholar 

  • 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 12:96–104

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 194:809–821

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lee YK, Turner H et al (2009) Late developmental plasticity in the T helper 17 lineage. Immunity 30:92–107

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 32:743–753

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 34:776–787

    CAS  PubMed  Google Scholar 

  • Levine JE (2011) Implications of TNF-alpha in the pathogenesis and management of GVHD. Int J Hematol 93:571–577

    CAS  PubMed Central  PubMed  Google Scholar 

  • Li QJ, Chau J et al (2007) miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129:147–161

    CAS  PubMed  Google Scholar 

  • 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 203:2271–2279

    CAS  PubMed Central  PubMed  Google Scholar 

  • Liao JK, Laufs U (2005) Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol 45:89–118

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lord GM, Rao RM et al (2005) T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood 106:3432–3439

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 97:1123–1130

    CAS  PubMed  Google Scholar 

  • Lu LF, Lind EF et al (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002

    CAS  PubMed  Google Scholar 

  • 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 112:5254–5258

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lu LF, Boldin MP et al (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142:914–929

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lu Y, Hong S et al (2012) Th9 cells promote antitumor immune responses in vivo. J Clin Invest 122:4160–4171

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 205:799–810

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 12:861–869

    CAS  PubMed  Google Scholar 

  • 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 121:2554–2569

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 268:37–46

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 4:765–772

    CAS  PubMed  Google Scholar 

  • Mangan PR, Harrington LE et al (2006) Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441:231–234

    CAS  PubMed  Google Scholar 

  • 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 12:623–634

    CAS  Google Scholar 

  • 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 39:216–224

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mathur AN, Chang HC et al (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901–4907

    CAS  PubMed  Google Scholar 

  • 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 5:179ra43

    Google Scholar 

  • 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 178:379–388

    CAS  PubMed  Google Scholar 

  • Mausner-Fainberg K, Luboshits G et al (2008) The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+ CD25+ T cells. Atherosclerosis 197:829–839

    CAS  PubMed  Google Scholar 

  • 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 10:314–324

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 90:3735–3739

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 22:2980–2993

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miura Y, Thoburn CJ et al (2004) Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 104:2187–2193

    CAS  PubMed  Google Scholar 

  • Monticelli S, Ansel KM et al (2005) MicroRNA profiling of the murine hematopoietic system. Genome Biol 6:R71

    PubMed Central  PubMed  Google Scholar 

  • Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173

    CAS  PubMed  Google Scholar 

  • 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 136:2348–2357

    CAS  PubMed  Google Scholar 

  • Muljo SA, Ansel KM et al (2005) Aberrant T cell differentiation in the absence of Dicer. J Exp Med 202:261–269

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mullen AC, High FA et al (2001) Role of T-bet in commitment of TH1 cells before IL-12-dependent selection. Science 292:1907–1910

    CAS  PubMed  Google Scholar 

  • 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 3:652–658

    CAS  PubMed  Google Scholar 

  • Muranski P, Boni A et al (2008) Tumor-specific Th17-polarized cells eradicate large established melanoma. Blood 112:362–373

    CAS  PubMed Central  PubMed  Google Scholar 

  • Murphy KM, Reiner SL (2002) The lineage decisions of helper T cells. Nat Rev Immunol 2:933–944

    CAS  PubMed  Google Scholar 

  • 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 102:1742–1748

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 29:979–986

    CAS  Google Scholar 

  • 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 105:1289–1298

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nishimori H, Maeda Y et al (2012) Synthetic retinoid Am 80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17. Blood 119:285–295

    CAS  PubMed  Google Scholar 

  • Nistala K, Adams S et al (2010) Th17 plasticity in human autoimmune arthritis is driven by the inflammatory environment. Proc Natl Acad Sci USA 107:14751–14756

    CAS  PubMed Central  PubMed  Google Scholar 

  • Noelle RJ, Nowak EC (2010) Cellular sources and immune functions of interleukin-9. Nat Rev Immunol 10:683–687

    CAS  PubMed  Google Scholar 

  • Nowak EC, Weaver CT et al (2009) IL-9 as a mediator of Th17-driven inflammatory disease. J Exp Med 206:1653–1660

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 29:138–149

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 208:1001–1013

    CAS  PubMed Central  PubMed  Google Scholar 

  • O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283

    PubMed  Google Scholar 

  • Oldenhove G, Bouladoux N et al (2009) Decrease of Foxp3+ Treg cell number and acquisition of effector cell phenotype during lethal infection. Immunity 31:772–786

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 13:715–725

    CAS  PubMed  Google Scholar 

  • Ouyang W, Kolls JK et al (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ouyang W, Rutz S et al (2011) Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 29:71–109

    CAS  PubMed  Google Scholar 

  • 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 101:1993–1998

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 86:4422–4429

    CAS  PubMed  Google Scholar 

  • Park H, Li Z et al (2005) A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 6:1133–1141

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 408:57–63

    CAS  PubMed  Google Scholar 

  • Peter C, Waldmann H et al (2010) mTOR signalling and metabolic regulation of T cell differentiation. Curr Opin Immunol 22:655–661

    CAS  PubMed  Google Scholar 

  • Pidala J, Anasetti C (2010) Can antigen-specific regulatory T cells protect against graft versus host disease and spare anti-malignancy alloresponse? Haematologica 95:660–665

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 15:881–885

    CAS  Google Scholar 

  • Pidala J, Perez L et al (2012) Ustekinumab demonstrates activity in glucocorticoid-refractory acute GVHD. Bone Marrow Transpl 47:747–748

    CAS  Google Scholar 

  • 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 184:764–774

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ranganathan P, Heaphy CE et al (2012) Regulation of acute graft-versus-host disease by microRNA-155. Blood 119:4786–4797

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ratajczak P, Janin A et al (2010) Th17/Treg ratio in human graft-versus-host disease. Blood 116:1165–1171

    CAS  PubMed Central  PubMed  Google Scholar 

  • Reddy P, Negrin R et al (2008) Mouse models of bone marrow transplantation. Biol Blood Marrow Transpl 14:129–135

    Google Scholar 

  • 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 101:2024–2032

    CAS  PubMed  Google Scholar 

  • 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 11:706–712

    CAS  Google Scholar 

  • Robb RJ, Hill GR (2012) The interferon-dependent orchestration of innate and adaptive immunity after transplantation. Blood 119:5351–5358

    CAS  PubMed  Google Scholar 

  • 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 135:81–90

    CAS  PubMed  Google Scholar 

  • 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 21:152–158

    Google Scholar 

  • 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 150:5445–5456

    CAS  PubMed  Google Scholar 

  • Roy J, Blazar BR et al (1995) The tissue expression of cytokines in human acute cutaneous graft-versus-host disease. Transplantation 60:343–348

    CAS  PubMed  Google Scholar 

  • Rubtsov YP, Niec RE et al (2010) Stability of the regulatory T cell lineage in vivo. Science 329:1667–1671

    CAS  PubMed  Google Scholar 

  • Saadoun D, Rosenzwajg M et al (2011) Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 365:2067–2077

    CAS  PubMed  Google Scholar 

  • Sakaguchi S (2005) Naturally arising Foxp3-expressing CD25+ CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol 6:345–352

    CAS  PubMed  Google Scholar 

  • 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 182:18–32

    CAS  PubMed  Google Scholar 

  • Sakaguchi S, Vignali DA et al (2013) The plasticity and stability of regulatory T cells. Nat Rev Immunol 13:461–467

    CAS  PubMed  Google Scholar 

  • 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 161:6480–6486

    CAS  PubMed  Google Scholar 

  • 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 192:1553–1562

    CAS  PubMed Central  PubMed  Google Scholar 

  • Schindler C, Plumlee C (2008) Inteferons pen the JAK-STAT pathway. Semin Cell Dev Biol 19:311–318

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 8:732–742

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 17:309–318

    CAS  Google Scholar 

  • Shi G, Cox CA et al (2008) Phenotype switching by inflammation-inducing polarized Th17 cells, but not by Th1 cells. J Immunol 181:7205–7213

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 380:630–633

    CAS  PubMed  Google Scholar 

  • 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 118:2342–2350

    CAS  PubMed  Google Scholar 

  • Shlomchik WD (2007) Graft-versus-host disease. Nat Rev Immunol 7:340–352

    CAS  PubMed  Google Scholar 

  • Socie G, Blazar BR (2009) Acute graft-versus-host disease: from the bench to the bedside. Blood 114:4327–4336

    CAS  PubMed Central  PubMed  Google Scholar 

  • Soligo M, Camperio C et al (2011) CD28 costimulation regulates FOXP3 in a RelA/NF-kappaB-dependent mechanism. Eur J Immunol 41:503–513

    CAS  PubMed  Google Scholar 

  • Soroosh P, Doherty TA (2009) Th9 and allergic disease. Immunology 127:450–458

    CAS  PubMed Central  PubMed  Google Scholar 

  • Staudt V, Bothur E et al (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33:192–202

    CAS  PubMed  Google Scholar 

  • Steiner DF, Thomas MF et al (2011) MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. Immunity 35:169–181

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 41:952–962

    CAS  PubMed  Google Scholar 

  • 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 11:1057–1062

    CAS  PubMed  Google Scholar 

  • Stritesky GL, Muthukrishnan R et al (2011) The transcription factor STAT3 is required for T helper 2 cell development. Immunity 34:39–49

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun Y, Varambally S et al (2011) Targeting of microRNA-142-3p in dendritic cells regulates endotoxin-induced mortality. Blood 117:6172–6183

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 189:2033–2042

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 190:4005–4013

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 203:1685–1691

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 83:2560–2569

    CAS  PubMed  Google Scholar 

  • Szabo SJ, Kim ST et al (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100:655–669

    CAS  PubMed  Google Scholar 

  • Takeda K, Tanaka T et al (1996) Essential role of Stat6 in IL-4 signalling. Nature 380:627–630

    CAS  PubMed  Google Scholar 

  • 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 165:6687–6691

    CAS  PubMed  Google Scholar 

  • 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 85:558–565

    CAS  PubMed  Google Scholar 

  • Tato CM, O’Shea JJ (2006) Immunology: what does it mean to be just 17? Nature 441:166–168

    CAS  PubMed  Google Scholar 

  • Tawara I, Maeda Y et al (2008) Combined Th2 cytokine deficiency in donor T cells aggravates experimental acute graft-vs-host disease. Exp Hematol 36:988–996

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tawara I, Koyama M et al (2011) Interleukin-6 modulates graft-versus-host responses after experimental allogeneic bone marrow transplantation. Clin Cancer Res 17:77–88

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 99:3493–3499

    CAS  PubMed  Google Scholar 

  • Thierfelder WE, Van Deursen JM et al (1996) Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature 382:171–174

    CAS  PubMed  Google Scholar 

  • 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 29:679–690

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tian T, Yu S et al (2013) Th22 and related cytokines in inflammatory and autoimmune diseases. Expert Opin Ther Targets 17:113–125

    CAS  PubMed  Google Scholar 

  • Tresoldi E, Dell’albani I et al (2011) Stability of human rapamycin-expanded CD4+ CD25+ T regulatory cells. Haematologica 96:1357–1365

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 323:1488–1492

    CAS  PubMed  Google Scholar 

  • 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 18:415–428

    CAS  PubMed  Google Scholar 

  • 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 122:225–261

    Google Scholar 

  • 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 24:179–189

    CAS  PubMed  Google Scholar 

  • Veldhoen M, Hirota K et al (2008a) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453:106–109

    CAS  PubMed  Google Scholar 

  • 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 9:1341–1346

    CAS  PubMed  Google Scholar 

  • Vincent K, Roy DC et al (2011) Next-generation leukemia immunotherapy. Blood 118:2951–2959

    CAS  PubMed  Google Scholar 

  • Vink A, Warnier G et al (1999) Interleukin 9-induced in vivo expansion of the B-1 lymphocyte population. J Exp Med 189:1413–1423

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 116:466–474

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 207:2479–2491

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 282:34605–34610

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 30:155–167

    PubMed Central  PubMed  Google Scholar 

  • 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 6:604–612

    CAS  Google Scholar 

  • Welniak LA, Blazar BR et al (2007) Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu Rev Immunol 25:139–170

    CAS  PubMed  Google Scholar 

  • 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 147:1–9

    PubMed  Google Scholar 

  • 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 159:1208–1215

    CAS  PubMed  Google Scholar 

  • Wilson CB, Rowell E et al (2009) Epigenetic control of T-helper-cell differentiation. Nat Rev Immunol 9:91–105

    CAS  PubMed  Google Scholar 

  • Wu B, Huang C et al (2008) IL-9 is associated with an impaired Th1 immune response in patients with tuberculosis. Clin Immunol 126:202–210

    CAS  PubMed  Google Scholar 

  • 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 196:969–977

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xiao X, Balasubramanian S et al (2012) OX40 signaling favors the induction of T(H)9 cells and airway inflammation. Nat Immunol 13:981–990

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 178:6725–6729

    CAS  PubMed  Google Scholar 

  • 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 99:4207–4215

    CAS  PubMed  Google Scholar 

  • Yang XO, Panopoulos AD et al (2007) STAT3 regulates cytokine-mediated generation of inflammatory helper T cells. J Biol Chem 282:9358–9363

    CAS  PubMed  Google Scholar 

  • Yang L, Anderson DE et al (2008a) IL-21 and TGF-beta are required for differentiation of human T(H)17 cells. Nature 454:350–352

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang XO, Nurieva R et al (2008b) Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 29:44–56

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yang XO, Pappu BP et al (2008c) T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma. Immunity 28:29–39

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 12:247–254

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yao Z, Fanslow WC et al (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3:811–821

    CAS  PubMed  Google Scholar 

  • Yi T, Zhao D et al (2008) Absence of donor Th17 leads to augmented Th1 differentiation and exacerbated acute graft-versus-host disease. Blood 112:2101–2110

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 114:3101–3112

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yu D, Rao S et al (2009) The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity 31:457–468

    CAS  PubMed  Google Scholar 

  • 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 118:5011–5020

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 43:2327–2337

    CAS  PubMed  Google Scholar 

  • 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 110:4588–4598

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang N, Pan HF et al (2011) Th22 in inflammatory and autoimmune disease: prospects for therapeutic intervention. Mol Cell Biochem 353:41–46

    CAS  PubMed  Google Scholar 

  • 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 41:514–526

    CAS  PubMed  Google Scholar 

  • 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 218:1505–1513

    CAS  PubMed  Google Scholar 

  • Zheng W, Flavell RA (1997) The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 89:587–596

    CAS  PubMed  Google Scholar 

  • Zheng Y, Chaudhry A et al (2009) Regulatory T-cell suppressor program co-opts transcription factor IRF4 to control T(H)2 responses. Nature 458:351–356

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 8:967–974

    CAS  PubMed  Google Scholar 

  • Zhou L, Lopes JE et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 166:7276–7281

    CAS  PubMed  Google Scholar 

  • Zhu J, Cote-Sierra J et al (2003) Stat5 activation plays a critical role in Th2 differentiation. Immunity 19:739–748

    CAS  PubMed  Google Scholar 

  • 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 5:1157–1165

    CAS  PubMed  Google Scholar 

  • 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 16:3–10

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

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).

Author information

Authors and Affiliations

  1. Cancer Biology PhD Program, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL, 33612, USA

    Jianing Fu

  2. Department of Pathology and Cell Biology, University of South Florida, Tampa, FL, 33612, USA

    Jessica Heinrichs

  3. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Jianing Fu, Jessica Heinrichs & Xue-Zhong Yu

  4. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Xue-Zhong Yu

Authors
  1. Jianing Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Heinrichs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xue-Zhong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xue-Zhong Yu.

About this article

Cite this article

Fu, J., Heinrichs, J. & Yu, XZ. Helper T-Cell Differentiation in Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation. Arch. Immunol. Ther. Exp. 62, 277–301 (2014). https://doi.org/10.1007/s00005-014-0284-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00005-014-0284-z

Keywords

Search

Navigation