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Cytokines and Autoimmune Diseases pp 25–48Cite as

Chromatin Remodeling and Transcriptional Regulation of Cytokine Gene Expression in T Cells

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Abstract

The activation of T cells by antigen leads to the expression of a large number of cytokines that are important for the correct orchestration of an immune response. The specific array of cytokines produced depends on the antigen that is encountered and the environment of the T cell at the time of that encounter. These cytokines range from those required for T cell proliferation (e.g., interleukin-2 [IL-2]), activators of other cells of the immune system (e.g., IL-4 or granulocyte-macrophage colony-stimulating factor [GM-CSF]), to negative modulators of cell function (e.g., IL-10 or TGB-β). The aberrant expression of thes cytokines can lead to immune related disease such as autoimmune disease or chronic inflammation and modulating the profile of cytokine expression or function has been long touted as a possible treatment for these diseases.

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References

  1. Lanzavecchia, A., Iezzi, G., and Viola, A. (1999) From TCR engagement to T cell activation: a kinetic view of T cell behavior. Cell 96, 1–4.

    Article  PubMed  CAS  Google Scholar 

  2. Sprent, J. (1999) Presidential address to the American Association of Immunologists. Stimulating naïve T cells. J. Immunol. 163, 4629–4636.

    PubMed  CAS  Google Scholar 

  3. Greenfield, E. A., Nguyen, K. A., and Kuchroo, V. K. (1998) CD28/B7 costimulation: a review. Crit. Rev. Immunol. 18, 389–418.

    Article  PubMed  CAS  Google Scholar 

  4. Chambers, C. A. and Allison, J. P. (1999) Costimulatory regulation of T cell function. Curr. Opin. Cell Biol. 11, 203–210.

    Article  PubMed  CAS  Google Scholar 

  5. Khoury, S., Sayegh, M. H., and Turka, L. A. (1999) Blocking costimulatory signals to induce transplantation tolerance and prevent autoimmune disease. Intl. Rev. Immunol. 18, 185–199.

    Article  CAS  Google Scholar 

  6. Abbas, A. K., Murphy, K. M., and Sherr, A. (1996) Functional diversity of helper T lymphocytes. Nature 383, 787–793.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  8. Lenardo, M., Chan, F. K-M., Hornung, F., McFarland, H., Siegel, R., Wang, J., et al. (1999) Mature T lymphocyte apoptosis-immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253.

    Article  PubMed  CAS  Google Scholar 

  9. Fitzpatrick, D. R. and Kelso, A. (1998) Independent regulation of cytokine genes in T cells: the paradox in the paradigm. Transplantation 65, 1–5.

    Article  PubMed  CAS  Google Scholar 

  10. Glimcher, L. and Singh, H. (1999) Transcription factors in lymphocyte development-T and B cells get together. Cell 96, 13–23.

    Article  PubMed  CAS  Google Scholar 

  11. Kuo, C. T. and Leiden, J. M. (1999) Transcriptional regulation of T lymphocyte development and function. Annu. Rev. Immunol. 17, 149–187.

    Article  PubMed  CAS  Google Scholar 

  12. Avots, A., Escher, C., Muller-Deubert, S., Neumann, M., and Serfling, E. (1995) The interplay between lymphoid-specific and ubiquitous transcription factors controls the expression of the interleukin 2 gene in T lymphocytes. Immunobiology 193, 254–258.

    Article  PubMed  CAS  Google Scholar 

  13. Jain, J., Loh, C., and Rao, A. (1995) Transcriptional regulation of the IL-2 gene. Curr. Opin. Immunol. 7, 333–342.

    Article  PubMed  CAS  Google Scholar 

  14. Shannon, M. F., Coles, L. S., Vadas, M. A., and Cockerill, P. N. (1997) Signals for activation of the GM-CSF promoter and enhancer in T cells. Crit. Rev. Immunol. 17, 301–323.

    Article  PubMed  CAS  Google Scholar 

  15. Brown, M. A. and Hural, J. (1997) Functions of IL-4 and control of its expression. Crit. Rev. Immunol. 17, 1–32.

    Article  PubMed  CAS  Google Scholar 

  16. Briegel, K., Hentsch, B., Pfeuffer, I., and Serfling, E. (1991) One base pair change abolishes the T cell-restricted activity of a kB-like proto-enhancer element from the interleukin 2 promoter. Nucleic Acids Res. 19, 5929–5936.

    Article  PubMed  CAS  Google Scholar 

  17. Hentsch, B., Mouzaki, A., Pfeuffer, I., Rungger, D., and Serfling, E. (1992) The weak, fine-tuned binding of ubiquitous transcription factors to the IL-2 enhancer contributes to its T cell-restricted activity. Nucleic Acids Res. 20, 2657–2665.

    Article  PubMed  CAS  Google Scholar 

  18. Rothenberg, E. V. and Ward, S. B. (1996) A dynamic assembly of diverse transcription factors integrates activation and cell-type information for interleukin-2 gene regulation. Proc. Natl. Acad. Sci. USA 93, 9358–9365.

    Article  PubMed  CAS  Google Scholar 

  19. Thomas, R. S., Tymms, M. J., McKinlay, L. H., Shannon, M. F., Seth, A., and Kola, I. (1997) ETS1, NF-kappaB and AP1 synergistically transactivate the human GM-CSF promoter. Oncogene 14, 2845–2855.

    Article  PubMed  CAS  Google Scholar 

  20. Rao, A. (1994) NF-ATp: a transcription factor required for the co-ordinate induction of several cytokine genes. Immunol. Today 15, 274–281.

    Article  PubMed  CAS  Google Scholar 

  21. Rao, A., Luo, C., and Hogan P. G. (1997) Transcription factors of the NFAT family: regulation and function. Annu. Rev. Immunol. 15, 707–747.

    Article  PubMed  CAS  Google Scholar 

  22. Cockerill, P. N., Bert, A. G., Jenkins, F., Ryan, G. R., Shannon, M. F., and Vadas, M. A. (1995) Human granulocyte-macrophage colony-stimulating factor enhancer function is associated with cooperative interactions between AP-1 and NFATp/c. Mol. Cell Biol. 15, 2071–2079.

    PubMed  CAS  Google Scholar 

  23. Shapiro, V. S., Truitt, K. E., Imboden, J. B., and Weiss, A. (1997) CD28 mediates transcriptional upregulation of the interleukin-2 (IL-2) promoter through a composite element containing the CD28RE and NF-IL-2B AP-1 sites. Mol. Cell Biol. 17, 4051–4058.

    PubMed  CAS  Google Scholar 

  24. Himes, S. R., Reeves, R., Attema, J., Nissen, M., Li, Y., and Shannon, M. F. (2000) The role of high-mobility group I(Y) proteins in expression of IL-2 and T cell proliferation. J. Immunol. 164, 3157–3168.

    PubMed  CAS  Google Scholar 

  25. Carey, M. (1998) The enhanceosome and transcriptional synergy. Cell 92, 5–8.

    Article  PubMed  CAS  Google Scholar 

  26. Merika, M., Williams, A. J., Chen, G., Collins, T., and Thanos, D. (1998) Recruitment of CBP/p300 by the IFNβ enhanceosome is required for synergistic activation of transcription. Mol. Cell 1, 277–287.

    Article  PubMed  CAS  Google Scholar 

  27. Kim, T. K., Kim, T. H., and Maniatis, T. (1998) Efficient recruitment of TFIIB and CBP-RNA polymerase II holoenzyme by an interferon-β enhanceosome in vitro. Proc. Natl. Acad. Sci. USA 95, 12,191–12,196.

    Article  PubMed  CAS  Google Scholar 

  28. Su, B., Jacinto, E., Hibi, M., Kallunki, T., Karin, M., and Ben-Neriah, Y. (1994) JNK is involved in signal integration during costimulation of T lymphocytes. Cell 77, 727–736.

    Article  PubMed  Google Scholar 

  29. Baldwin, A. S. (1996) The NF-κB and IκB proteins: new discoveries and insights. Anna. Rev. Immunol. 14, 649–683.

    Article  CAS  Google Scholar 

  30. Bryan, R. G., Li, Y., Lai, J. H., Van, M., Rice, N. R., Rich, R. R., et al. (1994) Effect of CD28 signal transduction on c-Rel in human peripheral blood T cells. Mol. Cell Biol. 14, 7933–7942.

    PubMed  CAS  Google Scholar 

  31. Himes, S. R., Coles, L. S., Reeves, R., and Shannon, M. F. (1996) High mobility group protein I(Y) is required for function and for c-Rel binding to CD28 response elements within the GM-CSF and IL-2 promoters. Immunity 5, 479–489.

    Article  PubMed  CAS  Google Scholar 

  32. Grumont, R. J., Richardson, I. B., Gaff, C., and Gerondakis, S. (1993) Rel/NF-κB nuclear complexes that bind κB sites in the murine c-rel promoter are required for constitutive c-rel transcription in B-cells. Cell Growth Differ. 4, 731–743.

    PubMed  CAS  Google Scholar 

  33. Lai, J.-H. and Tan, T.-H. (1994) CD28 signaling causes a sustained down-regulation of IκBα which can be prevented by the immunosuppressant rapamycin. J. Biol. Chem. 269, 30,077–30,080.

    PubMed  CAS  Google Scholar 

  34. Harhaj, E. W., Maggirwar, S. B., Good, L., and Sun, S.-C. (1996) CD28 mediates a potent costimulatory signal for rapid degradation of IκBβ which is associated with accelerated activation of various NF-κB/Rel heterodimers. Mol. Cell Biol. 16, 6736–6743.

    PubMed  CAS  Google Scholar 

  35. Kempiak, S. J., Hiura, T. S., and Nel, A. E. (1999) The Jun kinase cascade is responsible for activating the CD28 response element of the IL-2 promoter; proof of cross-talk with the IκB kinase cascade. J. Immunol. 162, 3176–3187.

    PubMed  CAS  Google Scholar 

  36. Butscher, W. G., Powers, C., Olive, M., Vinson, C., and Gardner, K. (1998) Coordinate transactivation of the interleukin-2 CD28 response element by c-Rel and ATF-1/CREB2. J. Biol. Chem. 273, 552–560.

    Article  PubMed  CAS  Google Scholar 

  37. Parra, E., McGuire, K., Hedlund, G., and Dohlsten, M. (1998) Overexpression of p65 and c-Jun substitutes for B7-1 costimulation by targeting the CD28RE within the IL-2 promoter. J. Immunol. 160, 5374–5381.

    PubMed  CAS  Google Scholar 

  38. McGuire, K. and Iacobelli, M. (1997) Involvement of Rel, Fos, and Jun proteins in binding activity to the IL-2 promoter CD28 response element/AP-1 sequence in human T cells. J. Immunol. 159, 1319–1327.

    PubMed  CAS  Google Scholar 

  39. Civil, A., Rensink, I., Aarden, L. A., and Verweij, C. L. (1999) Functional disparity of distinct CD28 response elements toward mitogenic responses. J. Biol. Chem. 274, 34,369–34,374.

    Article  PubMed  CAS  Google Scholar 

  40. Rooney, J. W., Sun, Y. L., Glimcher, L. H., and Hoey, T. (1995) Novel NFAT sites that mediate activation of the interleukin-2 promoter in response to T cell receptor stimulation. Mol. Cell Biol. 15, 6299–6310.

    PubMed  CAS  Google Scholar 

  41. Dunn, S. M., Coles, L. S., Lang, R. K., Gerondakis, S., Vadas, M. A., and Shannon, M. F. (1994) Requirement for nuclear factor (NF)-kappa B p65 and NF-interleukin-6 binding elements in the tumor necrosis factor response region of the granulocyte colony-stimulating factor promoter. Blood 83, 2469–2479.

    PubMed  CAS  Google Scholar 

  42. Kunsch, C., Lang, R. K., Rosen, C. A., and Shannon, M. F. (1994) Synergistic transcriptional activation of the IL-8 gene by NF-κB p65 (RelA) and NF-IL-6. J. Immunol. 153, 153–164.

    PubMed  CAS  Google Scholar 

  43. Catron, K. M., Brickwood, J. R., Shang, C., Li, Y., Shannon, M. F., and Parks, T. P. (1998) Cooperative binding and synergistic activation by RelA and C/ EBPβ on the intercellular adhesion molecule-1 promoter. Cell Growth Differ. 9, 949–959.

    PubMed  CAS  Google Scholar 

  44. Li-Weber, M., Giasi, M., and Krammer, P. H. (1998) Involvement of Jun and Rel proteins in up-regulation of interleukin-4 gene activity by the T cell accessory molecule CD28. J. Biol. Chem. 273, 32,460–32,466.

    Article  PubMed  CAS  Google Scholar 

  45. Keane-Myers, A., Gause, W. C., Linsley, P. S., Chen, S.-J., and Wills-Karp, M. (1997) B7-CD28/CTLA-4 costimulatory pathways are required for the development of T helper cell 2-mediated allergic airway responses to inhaled antigens. J. Immunol. 158, 2042–2049.

    PubMed  CAS  Google Scholar 

  46. Tsuyuki, S., Tsuyuki, J., Einsle, K., Kopf, M., and Coyle, A. J. (1997) Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness. J. Exp. Med. 185, 1671–1679.

    Article  PubMed  CAS  Google Scholar 

  47. Larché, M., Till, S. J., Haselden, B. M., North, J., Barkans, J., Corrigan, C. J., et al. (1998) Costimulation through CD86 is involved in airway antigen-presenting cell and T cell responses to allergen in atopic asthmatics. J. Immunol. 161, 6375–6382.

    PubMed  Google Scholar 

  48. Bustin, M. and Reeves, R. (1996) High-mobility-group chromosomal proteins: architectural components that facilitate chromatin function. Prog. Nucleic Acid Res. Mol. Biol. 54, 35–100.

    Article  PubMed  CAS  Google Scholar 

  49. John, S., Reeves, R. B., Lin, J.-X., Child, R., Leiden, J. M., Thompson, C. B., and Leonard, W. J. (1995) Regulation of cell type-specific interleukin-2 receptor α-chain gene expression: potential role of physical interactions between Elf-1, HMG-I(Y), and NF-κB family proteins. Mol. Cell Biol. 15, 1786–1796.

    PubMed  CAS  Google Scholar 

  50. John, S., Robbins, C. M., and Leonard, W. J. (1996) An IL-2 response element in the human IL-2 receptor a chain promoter is a composite element that binds Stat5, Elf-1, HMG-I(Y) and a GATA family protein. EMBO J. 15, 5627–5635.

    PubMed  CAS  Google Scholar 

  51. Klein-Hessling, S., Schneider, G., Heinfling, A., Chuvpilo, S., and Serfling, E. (1996) HMG I(Y) interferes with the DNA binding of NF-AT factors and the induction of the interleukin 4 promoter in T cells. Proc. Natl. Acad. Sci. USA 93, 15,311–15,316.

    Article  PubMed  CAS  Google Scholar 

  52. Wang, D.-Z., Ray, P., and Boothby, M. (1995) Interleukin 4-inducible phosphorylation of HMG-I(Y) is inhibited by rapamycin. J. Biol. Chem. 270, 22,924–22,932.

    Article  PubMed  CAS  Google Scholar 

  53. Schilham, M. W. and Clevers, H. (1998) HMG box containing transcription factors in lymphocyte differentiation. Semin. Immunol. 10, 127–132.

    Article  PubMed  CAS  Google Scholar 

  54. Ward, S. B., Hernandez-Hoyos, G., Chen, F., Waterman, M., Reeves, R., and Rothenberg, E. V. (1998) Chromatin remodeling of the interleukin-2 gene: distinct alterations in the proximal versus distal enhancer regions. Nucleic Acids Res. 26, 2923–2934.

    Article  PubMed  CAS  Google Scholar 

  55. Kornberg, R. D. and Lorch, Y. (1999) Twenty-five years of the nucleosome, fundamental particle of the eukaryote chromosome. Cell 98, 285–294.

    Article  PubMed  CAS  Google Scholar 

  56. Struhl, K. (1998) Histone acetylation and transcriptional regulatory mechanisms. Genes Develop. 12, 599–606.

    Article  PubMed  CAS  Google Scholar 

  57. Kadonaga, J. T. (1998) Eukaryotic transcription: an interlaced network of transcription factors and chromatin-modifying machines. Cell 92, 307–313.

    Article  PubMed  CAS  Google Scholar 

  58. Varga-Weisz, P. D. and Becker, P. B. (1998) Chromatin-remodeling factors: machines that regulate? Curr. Opin. Cell Biol. 10, 346–353.

    Article  PubMed  CAS  Google Scholar 

  59. Gusthin, D. and Wolffe, A. P. (1999) Transcriptional control: Swltched-on mobility. Curr. Biol. 9, R742–R746.

    Article  Google Scholar 

  60. Björklund, S., Almouzni, G., Davidson, I., Nightingale, K. P., and Weiss, K. (1999) Global transcription regulators of eukaryotes. Cell 96, 759–767.

    Article  PubMed  Google Scholar 

  61. Cockerill, P. N., Shannon, M. F., Bert, A. G., Ryan, G. R., and Vadas, M. A. (1993) The granulocyte-macrophage colony-stimulating factor/interleukin 3 locus is regulated by an inducible cyclosporin A-sensitive enhancer. Proc. Natl. Acad. Sci. USA 90, 2466–2470.

    Article  PubMed  CAS  Google Scholar 

  62. Duncliffe, K. N., Bert, A. G., Vadas, M. A., and Cockerill, P. N. (1997) A T cell-specific enhancer in the interleukin-3 locus is activated cooperatively by Oct and NFAT elements within a DNase I-hypersensitive site. Immunity 6, 175–185.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  64. Takemoto, N., Koyano-Nakagawa, N., Yokota, T., Arai, N., Miyatake, S., and Arai, K. (1998) Th2-specific DNase I-hypersensitive sites in the murine IL-13 and IL-4 intergenic region. Intl. Immunol. 10, 1981–1985.

    Article  CAS  Google Scholar 

  65. Weinmann, A. S., Plevy, S. E., and Smale, S. T. (1999) Rapid and selective remodeling of a positioned nucleosome during the induction of IL-12 p40 transcription. Immunity 11, 665–695.

    Article  PubMed  CAS  Google Scholar 

  66. Zhao, K., Wang, W., Rando, O. J., Xue, Y., Swiderek, K., Kuo, A., and Crabtree, G. R. (1998) Rapid and phosphoinositol-dependent binding of the SWI/SNF-like BAF complex to chromatin after T lymphocyte receptor signaling. Cell 95, 625–636.

    Article  PubMed  CAS  Google Scholar 

  67. Parekh, B. S. and Maniatis, T. (1999) Virus infection leads to localized hyperacetylation of histones H3 and H4 at the IFN-β promoter. Mol. Cell 3, 125–129.

    Article  PubMed  CAS  Google Scholar 

  68. Jones, P. L. and Wolffe, A. P. (1999) Relationships between chromatin organization and DNA methylation in determining gene expression. Semin. Cancer Biol. 9, 339–347.

    Article  PubMed  CAS  Google Scholar 

  69. Razin, A. (1998) CpG methylation, chromatin structure and gene silencing-a three-way connection. EMBO J. 17, 4905–4908.

    Article  PubMed  CAS  Google Scholar 

  70. Bird, A. P. and Wolffe, A. P. (1999) Methylation-induced repression-belts, braces, and chromatin. Cell 99, 451–454.

    Article  PubMed  CAS  Google Scholar 

  71. Penix, L. A., Sweetser, M. T., Weaver, W. M., Hoeffler, J. P., Kerppola, T. K., and Wilson, C. B. (1996) The proximal regulatory element of the interferon-γ promoter mediates selective expression in T cells. J. Biol. Chem. 271, 31,964–31,972.

    Article  PubMed  CAS  Google Scholar 

  72. Young, H. A., Ghosh, P., Ye, J., Lederer, J., Lichtman, A., Gerard, J. R., et al. (1994) Differentiation of the T helper phenotypes by analysis of the methylation state of the IFN-γ gene. J. Immunol. 153, 3603–3610.

    PubMed  CAS  Google Scholar 

  73. Melvin, A. J., McGurn, M. E., Bort, S. J., Gibson, C., and Lewis, D. B. (1995) Hypomethylation of the interferon-γ gene correlates with its expression by primary T-lineage cells. Eur. J. Immunol. 25, 426–430.

    Article  PubMed  CAS  Google Scholar 

  74. Fitzpatrick, D. R., Shirley, K. M., McDonald, L. E., Bielefeldt-Ohmann, H., Kay, G. F., and Kelso, A. (1998) Distinct methylation of the interferon γ (IFN-γ) and interleukin 3 (IL-3) genes in newly activated primary CD8+ T lymphocytes: regional IFN-γ promoter demethylation and mRNA expression are heritable in CD44high CD8+ T cells. J. Exp. Med. 188, 103–117.

    Article  PubMed  CAS  Google Scholar 

  75. Mikovits, J. A., Young, H. A., Vertino, P., Issa, J.-P. J., Pitha, P. A., Turcoski-Corrales, S., et al. (1998) Infection with human immunodeficiency virus type 1 upregulates DNA methyltransferase, resulting in de novo methylation of the gamma interferon (IFN-γ) promoter and subsequent downregulation of IFN-γ production. Mol. Cell Biol. 18, 5166–5177.

    PubMed  CAS  Google Scholar 

  76. Bird, J. J., Brown, D. R., Mullen, A. C., Moskowitz, N. H., Mahowald, M. A., Sider, J. R., et al. (1998) Helper T cell differentiation is controlled by the cell cycle. Immunity 9, 229–237.

    Article  PubMed  CAS  Google Scholar 

  77. Gett, A. V. and Hodgkin, P. D. (1998) Cell division regulates the T cell cytokine repertoire, revealing a mechanism underlying immune class regulation. Proc. Natl. Acad. Sci. USA 95, 9488–9493.

    Article  PubMed  CAS  Google Scholar 

  78. Richter, A., Löhning, M., and Radbruch, A. (1999) Instruction for cytokine expression in T helper lymphocytes in relation to proliferation and cell cycle progression. J. Exp. Med. 190, 1439–1450.

    Article  PubMed  CAS  Google Scholar 

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  1. M. Frances Shannon
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  2. Adele F. Holloway
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Editors and Affiliations

  1. Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Vijay K. Kuchroo DVM, PhD , David A. Hafler MD  & Lindsay B. Nicholson PhD, MB ,  & 

  2. Department of Immunology, Scripps Research Institute, La Jolla, CA, USA

    Nora Sarvetnick PhD

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© 2002 Humana Press Inc., Totowa, NJ

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Shannon, M.F., Holloway, A.F. (2002). Chromatin Remodeling and Transcriptional Regulation of Cytokine Gene Expression in T Cells. In: Kuchroo, V.K., Sarvetnick, N., Hafler, D.A., Nicholson, L.B. (eds) Cytokines and Autoimmune Diseases. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-129-9_2

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  • DOI: https://doi.org/10.1007/978-1-59259-129-9_2

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