Skip to main content
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1989 Mar;9(3):1041–1048. doi: 10.1128/mcb.9.3.1041

Complexity of the primary genetic response to mitogenic activation of human T cells.

P F Zipfel 1, S G Irving 1, K Kelly 1, U Siebenlist 1
PMCID: PMC362694  PMID: 2498643

Abstract

We describe the isolation and characterization of more than 60 novel cDNA clones that constitute part of the immediate genetic response to resting human peripheral blood T cells after mitogen activation. This primary response was highly complex, both in the absolute number of inducible genes and in the diversity of regulation. Although most of the genes expressed in activated T cells were shared with the activation response of normal human fibroblasts, a significant number were more restricted in tissue specificity and thus likely encode or effect the differentiated functions of activated T cells. The activatable genes could be further differentiated on the basis of kinetics of induction, response to cycloheximide, and sensitivity to the immunosuppressive drug cyclosporin A. It is of note that cyclosporin A inhibited the expression of more than 10 inducible genes, which suggests that this drug has a broad genetic mechanism of action.

Full text

PDF
1041

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Almendral J. M., Sommer D., Macdonald-Bravo H., Burckhardt J., Perera J., Bravo R. Complexity of the early genetic response to growth factors in mouse fibroblasts. Mol Cell Biol. 1988 May;8(5):2140–2148. doi: 10.1128/mcb.8.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alonso M. A., Weissman S. M. cDNA cloning and sequence of MAL, a hydrophobic protein associated with human T-cell differentiation. Proc Natl Acad Sci U S A. 1987 Apr;84(7):1997–2001. doi: 10.1073/pnas.84.7.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Aviv H., Leder P. Purification of biologically active globin messenger RNA by chromatography on oligothymidylic acid-cellulose. Proc Natl Acad Sci U S A. 1972 Jun;69(6):1408–1412. doi: 10.1073/pnas.69.6.1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burd P. R., Freeman G. J., Wilson S. D., Berman M., DeKruyff R., Billings P. R., Dorf M. E. Cloning and characterization of a novel T cell activation gene. J Immunol. 1987 Nov 1;139(9):3126–3131. [PubMed] [Google Scholar]
  5. Cantrell D. A., Smith K. A. The interleukin-2 T-cell system: a new cell growth model. Science. 1984 Jun 22;224(4655):1312–1316. doi: 10.1126/science.6427923. [DOI] [PubMed] [Google Scholar]
  6. Chan J. Y., Slamon D. J., Nimer S. D., Golde D. W., Gasson J. C. Regulation of expression of human granulocyte/macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1986 Nov;83(22):8669–8673. doi: 10.1073/pnas.83.22.8669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chavrier P., Zerial M., Lemaire P., Almendral J., Bravo R., Charnay P. A gene encoding a protein with zinc fingers is activated during G0/G1 transition in cultured cells. EMBO J. 1988 Jan;7(1):29–35. doi: 10.1002/j.1460-2075.1988.tb02780.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  9. Christmas S. E., Meager A., Moore M. Production of interferon and tumour necrosis factor by cloned human natural cytotoxic lymphocytes and T cells. Clin Exp Immunol. 1987 Aug;69(2):441–450. [PMC free article] [PubMed] [Google Scholar]
  10. Cochran B. H., Reffel A. C., Stiles C. D. Molecular cloning of gene sequences regulated by platelet-derived growth factor. Cell. 1983 Jul;33(3):939–947. doi: 10.1016/0092-8674(83)90037-5. [DOI] [PubMed] [Google Scholar]
  11. Cole M. D. The myc oncogene: its role in transformation and differentiation. Annu Rev Genet. 1986;20:361–384. doi: 10.1146/annurev.ge.20.120186.002045. [DOI] [PubMed] [Google Scholar]
  12. Cristofalo V. J., Sharf B. B. Cellular senescence and DNA synthesis. Thymidine incorporation as a measure of population age in human diploid cells. Exp Cell Res. 1973 Feb;76(2):419–427. doi: 10.1016/0014-4827(73)90394-7. [DOI] [PubMed] [Google Scholar]
  13. Cuturi M. C., Murphy M., Costa-Giomi M. P., Weinmann R., Perussia B., Trinchieri G. Independent regulation of tumor necrosis factor and lymphotoxin production by human peripheral blood lymphocytes. J Exp Med. 1987 Jun 1;165(6):1581–1594. doi: 10.1084/jem.165.6.1581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gershenfeld H. K., Weissman I. L. Cloning of a cDNA for a T cell-specific serine protease from a cytotoxic T lymphocyte. Science. 1986 May 16;232(4752):854–858. doi: 10.1126/science.2422755. [DOI] [PubMed] [Google Scholar]
  15. Granelli-Piperno A., Andrus L., Steinman R. M. Lymphokine and nonlymphokine mRNA levels in stimulated human T cells. Kinetics, mitogen requirements, and effects of cyclosporin A. J Exp Med. 1986 Apr 1;163(4):922–937. doi: 10.1084/jem.163.4.922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Greene W. C., Leonard W. J. The human interleukin-2 receptor. Annu Rev Immunol. 1986;4:69–95. doi: 10.1146/annurev.iy.04.040186.000441. [DOI] [PubMed] [Google Scholar]
  17. Gubler U., Hoffman B. J. A simple and very efficient method for generating cDNA libraries. Gene. 1983 Nov;25(2-3):263–269. doi: 10.1016/0378-1119(83)90230-5. [DOI] [PubMed] [Google Scholar]
  18. Hardy K. J., Manger B., Newton M., Stobo J. D. Molecular events involved in regulating human interferon-gamma gene expression during T cell activation. J Immunol. 1987 Apr 1;138(7):2353–2358. [PubMed] [Google Scholar]
  19. Hedrick S. M., Cohen D. I., Nielsen E. A., Davis M. M. Isolation of cDNA clones encoding T cell-specific membrane-associated proteins. Nature. 1984 Mar 8;308(5955):149–153. doi: 10.1038/308149a0. [DOI] [PubMed] [Google Scholar]
  20. Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. doi: 10.1038/324073a0. [DOI] [PubMed] [Google Scholar]
  21. Irving S. G., June C. H., Zipfel P. F., Siebenlist U., Kelly K. Mitogen-induced genes are subject to multiple pathways of regulation in the initial stages of T-cell activation. Mol Cell Biol. 1989 Mar;9(3):1034–1040. doi: 10.1128/mcb.9.3.1034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. June C. H., Ledbetter J. A., Gillespie M. M., Lindsten T., Thompson C. B. T-cell proliferation involving the CD28 pathway is associated with cyclosporine-resistant interleukin 2 gene expression. Mol Cell Biol. 1987 Dec;7(12):4472–4481. doi: 10.1128/mcb.7.12.4472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  24. Kelly K., Siebenlist U. The regulation and expression of c-myc in normal and malignant cells. Annu Rev Immunol. 1986;4:317–338. doi: 10.1146/annurev.iy.04.040186.001533. [DOI] [PubMed] [Google Scholar]
  25. Kwon B. S., Kim G. S., Prystowsky M. B., Lancki D. W., Sabath D. E., Pan J. L., Weissman S. M. Isolation and initial characterization of multiple species of T-lymphocyte subset cDNA clones. Proc Natl Acad Sci U S A. 1987 May;84(9):2896–2900. doi: 10.1073/pnas.84.9.2896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Larsson E. L. Cyclosporin A and dexamethasone suppress T cell responses by selectively acting at distinct sites of the triggering process. J Immunol. 1980 Jun;124(6):2828–2833. [PubMed] [Google Scholar]
  27. Lau L. F., Nathans D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc Natl Acad Sci U S A. 1987 Mar;84(5):1182–1186. doi: 10.1073/pnas.84.5.1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Lau L. F., Nathans D. Identification of a set of genes expressed during the G0/G1 transition of cultured mouse cells. EMBO J. 1985 Dec 1;4(12):3145–3151. doi: 10.1002/j.1460-2075.1985.tb04057.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lobe C. G., Havele C., Bleackley R. C. Cloning of two genes that are specifically expressed in activated cytotoxic T lymphocytes. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1448–1452. doi: 10.1073/pnas.83.5.1448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Milbrandt J. A nerve growth factor-induced gene encodes a possible transcriptional regulatory factor. Science. 1987 Nov 6;238(4828):797–799. doi: 10.1126/science.3672127. [DOI] [PubMed] [Google Scholar]
  31. Mustelin T., Pösö H., Lapinjoki S. P., Gynther J., Andersson L. C. Growth signal transduction: rapid activation of covalently bound ornithine decarboxylase during phosphatidylinositol breakdown. Cell. 1987 Apr 24;49(2):171–176. doi: 10.1016/0092-8674(87)90557-5. [DOI] [PubMed] [Google Scholar]
  32. Müller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factors precedes activation of c-myc. Nature. 1984 Dec 20;312(5996):716–720. doi: 10.1038/312716a0. [DOI] [PubMed] [Google Scholar]
  33. Reed J. C., Abidi A. H., Alpers J. D., Hoover R. G., Robb R. J., Nowell P. C. Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression. J Immunol. 1986 Jul 1;137(1):150–154. [PubMed] [Google Scholar]
  34. Reed J. C., Alpers J. D., Nowell P. C., Hoover R. G. Sequential expression of protooncogenes during lectin-stimulated mitogenesis of normal human lymphocytes. Proc Natl Acad Sci U S A. 1986 Jun;83(11):3982–3986. doi: 10.1073/pnas.83.11.3982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Reed J. C., Tsujimoto Y., Alpers J. D., Croce C. M., Nowell P. C. Regulation of bcl-2 proto-oncogene expression during normal human lymphocyte proliferation. Science. 1987 Jun 5;236(4806):1295–1299. doi: 10.1126/science.3495884. [DOI] [PubMed] [Google Scholar]
  36. Reem G. H., Cook L. A., Vilcek J. Gamma interferon synthesis by human thymocytes and T lymphocytes inhibited by cyclosporin A. Science. 1983 Jul 1;221(4605):63–65. doi: 10.1126/science.6407112. [DOI] [PubMed] [Google Scholar]
  37. Schmid J., Weissmann C. Induction of mRNA for a serine protease and a beta-thromboglobulin-like protein in mitogen-stimulated human leukocytes. J Immunol. 1987 Jul 1;139(1):250–256. [PubMed] [Google Scholar]
  38. Sukhatme V. P., Cao X. M., Chang L. C., Tsai-Morris C. H., Stamenkovich D., Ferreira P. C., Cohen D. R., Edwards S. A., Shows T. B., Curran T. A zinc finger-encoding gene coregulated with c-fos during growth and differentiation, and after cellular depolarization. Cell. 1988 Apr 8;53(1):37–43. doi: 10.1016/0092-8674(88)90485-0. [DOI] [PubMed] [Google Scholar]
  39. Sukhatme V. P., Kartha S., Toback F. G., Taub R., Hoover R. G., Tsai-Morris C. H. A novel early growth response gene rapidly induced by fibroblast, epithelial cell and lymphocyte mitogens. Oncogene Res. 1987 Sep-Oct;1(4):343–355. [PubMed] [Google Scholar]
  40. Weiss A., Imboden J. B. Cell surface molecules and early events involved in human T lymphocyte activation. Adv Immunol. 1987;41:1–38. doi: 10.1016/s0065-2776(08)60029-2. [DOI] [PubMed] [Google Scholar]
  41. Weiss A., Shields R., Newton M., Manger B., Imboden J. Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene. J Immunol. 1987 Apr 1;138(7):2169–2176. [PubMed] [Google Scholar]
  42. Yang Y. C., Ciarletta A. B., Temple P. A., Chung M. P., Kovacic S., Witek-Giannotti J. S., Leary A. C., Kriz R., Donahue R. E., Wong G. G. Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell. 1986 Oct 10;47(1):3–10. doi: 10.1016/0092-8674(86)90360-0. [DOI] [PubMed] [Google Scholar]
  43. Yokota T., Coffman R. L., Hagiwara H., Rennick D. M., Takebe Y., Yokota K., Gemmell L., Shrader B., Yang G., Meyerson P. Isolation and characterization of lymphokine cDNA clones encoding mouse and human IgA-enhancing factor and eosinophil colony-stimulating factor activities: relationship to interleukin 5. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7388–7392. doi: 10.1073/pnas.84.21.7388. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yokota T., Otsuka T., Mosmann T., Banchereau J., DeFrance T., Blanchard D., De Vries J. E., Lee F., Arai K. Isolation and characterization of a human interleukin cDNA clone, homologous to mouse B-cell stimulatory factor 1, that expresses B-cell- and T-cell-stimulating activities. Proc Natl Acad Sci U S A. 1986 Aug;83(16):5894–5898. doi: 10.1073/pnas.83.16.5894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zurawski G., Benedik M., Kamb B. J., Abrams J. S., Zurawski S. M., Lee F. D. Activation of mouse T-helper cells induces abundant preproenkephalin mRNA synthesis. Science. 1986 May 9;232(4751):772–775. doi: 10.1126/science.2938259. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES