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  • Original Article
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Immunology

Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells

Leukemia volume 22, pages 2201–2207 (2008)Cite this article

A Corrigendum to this article was published on 17 December 2008

Abstract

On activation, umbilical cord blood (UCB) CD4+ T cells demonstrate reduced expression of tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), whereas maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4+ T cells. Nuclear factor of activated T cells (NFAT1) protein, a transcription factor known to regulate the expression of IL-2, TNF-α and IFN-γ, is reduced in resting and activated UCB CD4+ T cells. In contrast, expression of Broad-complex-Tramtrack-Bric-a-Brac and Cap‘n’collar homology 1 bZip transcription factor 2 (BACH2) was shown by gene array analyses to be increased in UCB CD4+ T cells and was validated by qRT-PCR. Using chromatin immunoprecipitation, BACH2 was shown binding to the human IL-2 proximal promoter. Knockdown experiments of BACH2 by transient transfection of UCB CD4+ T cells with BACH2 siRNA resulted in significant reductions in stimulated IL-2 production. Decreased IL-2 gene transcription in UCB CD4+ T cells transfected with BACH2 siRNA was confirmed by a human IL-2 luciferase assay. In summary, BACH2 maintains IL-2 expression in UCB CD4+ T cells at levels equivalent to adult PB CD4+ T cells despite reduced NFAT1 protein expression. Thus, BACH2 expression is necessary to maintain IL-2 production when NFAT1 protein is reduced, potentially impacting UCB graft CD4+ T-cell allogeneic responses.

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References

  1. Chalmers I, Janossy G, Contreras M, Navarrete C . Intracellular cytokine profile of cord and adult blood lymphocytes. Blood 1998; 92: 11–18.

    CAS  PubMed  Google Scholar 

  2. Risdon G, Gaddy J, Stehman FB, Broxmeyer HE . Proliferative and cytotoxic responses of human cord blood T lymphocytes following allogeneic stimulation. Cell Immunol 1994; 154: 14–24.

    Article  CAS  PubMed  Google Scholar 

  3. Kadereit S, Kozik MM, Junge GR, Miller RE, Slivka LF, Bos LS et al. Cyclosporin A effects during primary and secondary activation of human umbilical cord blood T lymphocytes. Exp Hematol 2001; 29: 903–909.

    Article  CAS  PubMed  Google Scholar 

  4. Risdon G, Gaddy J, Broxmeyer HE . Allogeneic responses of human umbilical cord blood. Blood Cells 1994; 20: 566–570; discussion 571–562.

    CAS  PubMed  Google Scholar 

  5. Porcu P, Gaddy J, Broxmeyer HE . Alloantigen-induced unresponsiveness in cord blood T lymphocytes is associated with defective activation of Ras. Proc Natl Acad Sci USA 1998; 95: 4538–4543.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kaminski BA, Kadereit S, Miller RE, Leahy P, Stein KR, Topa DA et al. Reduced expression of NFAT-associated genes in UCB versus adult CD4+ T lymphocytes during primary stimulation. Blood 2003; 102: 4608–4617.

    Article  CAS  PubMed  Google Scholar 

  7. Canto E, Rodriguez-Sanchez JL, Vidal S . Naive CD4+ cells from cord blood can generate competent Th effector cells. Transplantation 2005; 80: 850–858.

    Article  PubMed  Google Scholar 

  8. Andersson J, Stefanova I, Stephens GL, Shevach EM . CD4+CD25+ regulatory T cells are activated in vivo by recognition of self. Int Immunol 2007; 19: 557–566.

    Article  CAS  PubMed  Google Scholar 

  9. Krampera M, Tavecchia L, Benedetti F, Nadali G, Pizzolo G . Intracellular cytokine profile of cord blood T-, and NK-cells and monocytes. Haematologica 2000; 85: 675–679.

    CAS  PubMed  Google Scholar 

  10. Bachmann MF, Oxenius A . Interleukin 2: from immunostimulation to immunoregulation and back again. EMBO Rep 2007; 8: 1142–1148.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH . Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev 1998; 165: 287–300.

    Article  CAS  PubMed  Google Scholar 

  12. Wolf M, Schimpl A, Hunig T . Control of T-cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(−) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms. Eur J Immunol 2001; 31: 1637–1645.

    Article  CAS  PubMed  Google Scholar 

  13. Bosque A, Marzo I, Naval J, Anel A . Apoptosis by IL-2 deprivation in human CD8+ T-cell blasts predominates over death receptor ligation, requires Bim expression and is associated with Mcl-1 loss. Mol Immunol 2007; 44: 1446–1453.

    Article  CAS  PubMed  Google Scholar 

  14. Long SA, Buckner JH . Combination of rapamycin and IL-2 increases de novo induction of human CD4(+)CD25(+)FOXP3(+) T cells. J Autoimmun 2008; 30: 293–302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jain J, Loh C, Rao A . Transcriptional regulation of the IL-2 gene. Curr Opin Immunol 1995; 7: 333–342.

    Article  CAS  PubMed  Google Scholar 

  16. Jain J, Valge-Archer VE, Rao A . Analysis of the AP-1 sites in the IL-2 promoter. J Immunol 1992; 148: 1240–1250.

    CAS  PubMed  Google Scholar 

  17. Chen L, Glover JN, Hogan PG, Rao A, Harrison SC . Structure of the DNA-binding domains from NFAT, Fos and Jun bound specifically to DNA. Nature 1998; 392: 42–48.

    Article  CAS  PubMed  Google Scholar 

  18. Chen L, Oakley MG, Glover JN, Jain J, Dervan PB, Hogan PG et al. Only one of the two DNA-bound orientations of AP-1 found in solution cooperates with NFATp. Curr Biol 1995; 5: 882–889.

    Article  CAS  PubMed  Google Scholar 

  19. Diebold RJ, Rajaram N, Leonard DA, Kerppola TK . Molecular basis of cooperative DNA bending and oriented heterodimer binding in the NFAT1–Fos–Jun–ARRE2 complex. Proc Natl Acad Sci USA 1998; 95: 7915–7920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kadereit S, Mohammad SF, Miller RE, Woods KD, Listrom CD, McKinnon K et al. Reduced NFAT1 protein expression in human umbilical cord blood T lymphocytes. Blood 1999; 94: 3101–3107.

    CAS  PubMed  Google Scholar 

  21. Sterkers G, Henin Y, Kalil J, Bagot M, Levy JP . Influence of HLA class I- and class II-specific monoclonal antibodies on DR-restricted lymphoproliferative responses. I. Unseparated populations of effector cells. J Immunol 1983; 131: 2735–2740.

    CAS  PubMed  Google Scholar 

  22. Frandji P, Tkaczyk C, Oskeritzian C, David B, Desaymard C, Mecheri S . Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes. Eur J Immunol 1996; 26: 2517–2528.

    Article  CAS  PubMed  Google Scholar 

  23. Pfaffl MW, Horgan GW, Dempfle L . Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucl Acids Res 2002; 30: e36.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Mitchell CA, Jefferson AB, Bejeck BE, Brugge JS, Deuel TF, Majerus PW . Thrombin-stimulated immunoprecipitation of phosphatidylinositol 3-kinase from human platelets. Proc Natl Acad Sci USA 1990; 87: 9396–9400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schug J . Current Protocols in Bioinformatics. Wiley: Hoboken, 2003.

    Google Scholar 

  26. Oyake T, Itoh K, Motohashi H, Hayashi N, Hoshino H, Nishizawa M et al. Bach proteins belong to a novel family of BTB-basic leucine zipper transcription factors that interact with MafK and regulate transcription through the NF-E2 site. Mol Cell Biol 1996; 16: 6083–6095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bhaumik SR, Green MR . Interaction of Gal4p with components of transcription machinery in vivo. Methods Enzymol 2003; 370: 445–454.

    Article  CAS  PubMed  Google Scholar 

  28. Chuvpilo S, Avots A, Berberich-Siebelt F, Glockner J, Fischer C, Kerstan A et al. Multiple NF-ATc isoforms with individual transcriptional properties are synthesized in T lymphocytes. J Immunol 1999; 162: 7294–7301.

    CAS  PubMed  Google Scholar 

  29. Muckenfuss H, Hamdorf M, Avots A, Sanzenbacher R, Tschulena U, Cichutek K et al. IL-2 induction by simian immunodeficiency virus involves MAP kinase signaling but is independent of calcineurin/NF-AT activity. Mol Immunol 2006; 43: 1172–1182.

    Article  CAS  PubMed  Google Scholar 

  30. Jain J, McCaffrey PG, Miner Z, Kerppola TK, Lambert JN, Verdine GL et al. The T-cell transcription factor NFATp is a substrate for calcineurin and interacts with Fos and Jun. Nature 1993; 365: 352–355.

    Article  CAS  PubMed  Google Scholar 

  31. D'Arena G, Musto P, Cascavilla N, Di Giorgio G, Fusilli S, Zendoli F et al. Flow cytometric characterization of human umbilical cord blood lymphocytes: immunophenotypic features. Haematologica 1998; 83: 197–203.

    CAS  PubMed  Google Scholar 

  32. Garcia Vela JA, Delgado I, Bornstein R, Alvarez B, Auray MC, Martin I et al. Comparative intracellular cytokine production by in vitro stimulated T lymphocytes from human umbilical cord blood (HUCB) and adult peripheral blood (APB). Anal Cell Pathol 2000; 20: 93–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ahmadzadeh M, Rosenberg SA . IL-2 administration increases CD4+ CD25(hi) Foxp3+ regulatory T cells in cancer patients. Blood 2006; 107: 2409–2414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Malek TR, Bayer AL . Tolerance, not immunity, crucially depends on IL-2. Nat Rev 2004; 4: 665–674.

    Article  CAS  Google Scholar 

  35. Muto A, Hoshino H, Madisen L, Yanai N, Obinata M, Karasuyama H et al. Identification of Bach2 as a B-cell-specific partner for small maf proteins that negatively regulate the immunoglobulin heavy chain gene 3′ enhancer. EMBO J 1998; 17: 5734–5743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Sasaki S, Ito E, Toki T, Maekawa T, Kanezaki R, Umenai T et al. Cloning and expression of human B cell-specific transcription factor BACH2 mapped to chromosome 6q15. Oncogene 2000; 19: 3739–3749.

    Article  CAS  PubMed  Google Scholar 

  37. Vieira SA, Deininger MW, Sorour A, Sinclair P, Foroni L, Goldman JM et al. Transcription factor BACH2 is transcriptionally regulated by the BCR/ABL oncogene. Genes Chromosomes Cancer 2001; 32: 353–363.

    Article  CAS  PubMed  Google Scholar 

  38. Muto A, Tashiro S, Tsuchiya H, Kume A, Kanno M, Ito E et al. Activation of Maf/AP-1 repressor Bach2 by oxidative stress promotes apoptosis and its interaction with promyelocytic leukemia nuclear bodies. J Biol Chem 2002; 277: 20724–20733.

    Article  CAS  PubMed  Google Scholar 

  39. Hoshino H, Igarashi K . Expression of the oxidative stress-regulated transcription factor bach2 in differentiating neuronal cells. J Biochem (Tokyo) 2002; 132: 427–431.

    Article  CAS  Google Scholar 

  40. Muto A, Tashiro S, Nakajima O, Hoshino H, Takahashi S, Sakoda E et al. The transcriptional programme of antibody class switching involves the repressor BACH2. Nature 2004; 429: 566–571.

    Article  CAS  PubMed  Google Scholar 

  41. Sakane-Ishikawa E, Nakatsuka S, Tomita Y, Fujita S, Nakamichi I, Takakuwa T et al. Prognostic significance of BACH2 expression in diffuse large B-cell lymphoma: a study of the Osaka Lymphoma Study Group. J Clin Oncol 2005; 23: 8012–8017.

    Article  CAS  PubMed  Google Scholar 

  42. Chen W, Zhang W, Zhu J . [Homozygous deletion and methylation of p16 and p15 gene in acute leukemia]. Zhonghua xue ye xue za zhi=Zhonghua xueyexue zazhi 1999; 20: 474–476.

    CAS  PubMed  Google Scholar 

  43. Kadereit S, Junge GR, Kleen T, Kozik MM, Kaminski BA, Daum-Woods K et al. Deficient IFN-gamma expression in umbilical cord blood (UCB) T cells can be rescued by IFN-gamma-mediated increase in NFATc2 expression. J Clin Immunol 2003; 23: 485–497.

    Article  CAS  PubMed  Google Scholar 

  44. Kleen TO, Kadereit S, Fanning LR, Jaroscak J, Fu P, Meyerson HJ et al. Recipient-specific tolerance after HLA-mismatched umbilical cord blood stem cell transplantation. Transplantation 2005; 80: 1316–1322.

    Article  PubMed  Google Scholar 

  45. Han S, Williams S, Mustelin T . Cytoskeletal protein tyrosine phosphatase PTPH1 reduces T cell antigen receptor signaling. Eur J Immunol 2000; 30: 1318–1325.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr A Avots of the Pathologisches Institut, Würzburg, Germany, for his generous donation of the human IL-2 promoter plasmid construct. We also thank Abraham J and Phyllis Katz Foundation, Fannie E Rippel Foundation and Dr Donald and Ruth Weber Goodman Philanthropic Fund for their generous financial contribution to our laboratory.

Funding: This work was supported by RO1-AI47289-01 (MJL), NIH/NCI 5T32 CA059366-13 Research Oncology Training Grant (MLL). This research was supported by the Gene Expression and Genotyping Facility of the Case Comprehensive Cancer Center 5P30CA043703 (ClinicalTrials.gov identifier: NCT00003335), Abraham J and Phyllis Katz Foundation, Fannie E Rippel Foundation and Dr Donald and Ruth Weber Goodman Philanthropic Fund (MJL).

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Authors and Affiliations

  1. Department of Medicine, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    M L Lesniewski, P Haviernik, R P Weitzel, M M Kozik, L R Fanning, Y Hegerfeldt, M R Finney, N Greco & M J Laughlin

  2. Department of Biology, University of Konstanz, Konstanz, Germany

    S Kadereit

  3. Biochemistry, Case Comprehensive Cancer Center, Cleveland, OH, USA

    Y C Yang

  4. Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    M Z Ratajczak

  5. Abraham J and Phyllis Katz Cord Blood Foundation, Cleveland Cord Blood Center, Cleveland, OH, USA

    N Greco, P Paul & M J Laughlin

  6. Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Foundation Taussig Cancer Center, Cleveland, OH, USA

    J Maciejewski

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Lesniewski, M., Haviernik, P., Weitzel, R. et al. Regulation of IL-2 expression by transcription factor BACH2 in umbilical cord blood CD4+ T cells. Leukemia 22, 2201–2207 (2008). https://doi.org/10.1038/leu.2008.234

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