Skip to main content
The EMBO Journal logoLink to The EMBO Journal
. 1990 Jun;9(6):1867–1872. doi: 10.1002/j.1460-2075.1990.tb08312.x

Transcriptional and post-transcriptional regulation of TcR, CD4 and CD8 gene expression during activation of normal human T lymphocytes.

F Paillard 1, G Sterkers 1, C Vaquero 1
PMCID: PMC551892  PMID: 2140772

Abstract

We previously showed that the turnover rates of the messengers coding for the T cell receptor (TcR) alpha, beta and gamma, CD4 and CD8 molecules composing the multireceptor complex vary in normal human mature T lymphocytes according to their state of activation. Activation by soluble anti-CD3 which does not induce proliferation, promotes a weak up-modulation of the corresponding five mRNAs. In contrast, activation signals such as anti-CD3 + PMA, which lead to lymphokine mRNA expression and T cell proliferation, promote a decrease of the TcR, CD4 and CD8 mRNA levels within 4 h post-activation, followed by their gradual re-expression. Here we show that the down-modulation of these mRNAs results from early regulation controls at transcriptional and post-transcriptional levels, i.e. through a concomitant inhibition of transcription and destabilization of the mRNA. Moreover, later re-expression of the mRNA results from recovery of transcription and marked increase of the mRNA stability. Finally, down-modulation is specific for TcR, CD4 and CD8 mRNAs, all submitted to similar regulation processes. These results strongly suggest a direct correlation between down-modulation of the multireceptor complex mRNAs, and lymphokine mRNA expression, and cellular proliferation.

Full text

PDF
1871

Images in this article

Selected References

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

  1. Alexander D. R., Cantrell D. A. Kinases and phosphatases in T-cell activation. Immunol Today. 1989 Jun;10(6):200–205. doi: 10.1016/0167-5699(89)90325-3. [DOI] [PubMed] [Google Scholar]
  2. Anderson S. J., Chou H. S., Loh D. Y. A conserved sequence in the T-cell receptor beta-chain promoter region. Proc Natl Acad Sci U S A. 1988 May;85(10):3551–3554. doi: 10.1073/pnas.85.10.3551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barber E. K., Dasgupta J. D., Schlossman S. F., Trevillyan J. M., Rudd C. E. The CD4 and CD8 antigens are coupled to a protein-tyrosine kinase (p56lck) that phosphorylates the CD3 complex. Proc Natl Acad Sci U S A. 1989 May;86(9):3277–3281. doi: 10.1073/pnas.86.9.3277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Barbu V., Dautry F. Northern blot normalization with a 28S rRNA oligonucleotide probe. Nucleic Acids Res. 1989 Sep 12;17(17):7115–7115. doi: 10.1093/nar/17.17.7115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blue M. L., Hafler D. A., Craig K. A., Levine H., Schlossman S. F. Phosphorylation of CD4 and CD8 molecules following T cell triggering. J Immunol. 1987 Dec 15;139(12):3949–3954. [PubMed] [Google Scholar]
  6. Borst J., van de Griend R. J., van Oostveen J. W., Ang S. L., Melief C. J., Seidman J. G., Bolhuis R. L. A T-cell receptor gamma/CD3 complex found on cloned functional lymphocytes. Nature. 1987 Feb 19;325(6106):683–688. doi: 10.1038/325683a0. [DOI] [PubMed] [Google Scholar]
  7. Brenner M. B., Trowbridge I. S., Strominger J. L. Cross-linking of human T cell receptor proteins: association between the T cell idiotype beta subunit and the T3 glycoprotein heavy subunit. Cell. 1985 Jan;40(1):183–190. doi: 10.1016/0092-8674(85)90321-6. [DOI] [PubMed] [Google Scholar]
  8. Brewer G., Ross J. Regulation of c-myc mRNA stability in vitro by a labile destabilizer with an essential nucleic acid component. Mol Cell Biol. 1989 May;9(5):1996–2006. doi: 10.1128/mcb.9.5.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cantrell D., Davies A. A., Londei M., Feldman M., Crumpton M. J. Association of phosphorylation of the T3 antigen with immune activation of T lymphocytes. Nature. 1987 Feb 5;325(6104):540–542. doi: 10.1038/325540a0. [DOI] [PubMed] [Google Scholar]
  10. Carrel S., Moretta A., Pantaleo G., Tambussi G., Isler P., Perussia B., Cerottini J. C. Stimulation and proliferation of CD4+ peripheral blood T lymphocytes induced by an anti-CD4 monoclonal antibody. Eur J Immunol. 1988 Mar;18(3):333–339. doi: 10.1002/eji.1830180303. [DOI] [PubMed] [Google Scholar]
  11. Emmrich F. Cross-linking of CD4 and CD8 with the T-cell receptor complex: quaternary complex formation and T-cell repertoire selection. Immunol Today. 1988 Oct;9(10):296–300. doi: 10.1016/0167-5699(88)91320-5. [DOI] [PubMed] [Google Scholar]
  12. Hadden J. W. Transmembrane signals in the activation of T lymphocytes by mitogenic antigens. Immunol Today. 1988 Jul-Aug;9(7-8):235–239. doi: 10.1016/0167-5699(88)91222-4. [DOI] [PubMed] [Google Scholar]
  13. Heckford S. E., Gelmann E. P., Agnor C. L., Jacobson S., Zinn S., Matis L. A. Distinct signals are required for proliferation and lymphokine gene expression in murine T cell clones. J Immunol. 1986 Dec 1;137(11):3652–3663. [PubMed] [Google Scholar]
  14. Hood L., Kronenberg M., Hunkapiller T. T cell antigen receptors and the immunoglobulin supergene family. Cell. 1985 Feb;40(2):225–229. doi: 10.1016/0092-8674(85)90133-3. [DOI] [PubMed] [Google Scholar]
  15. Hoxie J. A., Matthews D. M., Callahan K. J., Cassel D. L., Cooper R. A. Transient modulation and internalization of T4 antigen induced by phorbol esters. J Immunol. 1986 Aug 15;137(4):1194–1201. [PubMed] [Google Scholar]
  16. Kuziel W. A., Takashima A., Bonyhadi M., Bergstresser P. R., Allison J. P., Tigelaar R. E., Tucker P. W. Regulation of T-cell receptor gamma-chain RNA expression in murine Thy-1+ dendritic epidermal cells. Nature. 1987 Jul 16;328(6127):263–266. doi: 10.1038/328263a0. [DOI] [PubMed] [Google Scholar]
  17. Leonard W. J., Depper J. M., Crabtree G. R., Rudikoff S., Pumphrey J., Robb R. J., Krönke M., Svetlik P. B., Peffer N. J., Waldmann T. A. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature. 1984 Oct 18;311(5987):626–631. doi: 10.1038/311626a0. [DOI] [PubMed] [Google Scholar]
  18. Lindsten T., June C. H., Thompson C. B. Transcription of T cell antigen receptor genes is induced by protein kinase C activation. J Immunol. 1988 Sep 1;141(5):1769–1774. [PubMed] [Google Scholar]
  19. Littman D. R., Thomas Y., Maddon P. J., Chess L., Axel R. The isolation and sequence of the gene encoding T8: a molecule defining functional classes of T lymphocytes. Cell. 1985 Feb;40(2):237–246. doi: 10.1016/0092-8674(85)90138-2. [DOI] [PubMed] [Google Scholar]
  20. Luria S., Gross G., Horowitz M., Givol D. Promoter and enhancer elements in the rearranged alpha chain gene of the human T cell receptor. EMBO J. 1987 Nov;6(11):3307–3312. doi: 10.1002/j.1460-2075.1987.tb02650.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. MacDonald H. R., Glasebrook A. L., Bron C., Kelso A., Cerottini J. C. Clonal heterogeneity in the functional requirement for Lyt-2/3 molecules on cytolytic T lymphocytes (CTL): possible implications for the affinity of CTL antigen receptors. Immunol Rev. 1982;68:89–115. doi: 10.1111/j.1600-065x.1982.tb01061.x. [DOI] [PubMed] [Google Scholar]
  22. Maddon P. J., Littman D. R., Godfrey M., Maddon D. E., Chess L., Axel R. The isolation and nucleotide sequence of a cDNA encoding the T cell surface protein T4: a new member of the immunoglobulin gene family. Cell. 1985 Aug;42(1):93–104. doi: 10.1016/s0092-8674(85)80105-7. [DOI] [PubMed] [Google Scholar]
  23. Martinez-Valdez H., Doherty P. J., Thompson E., Benedict S. H., Gelfand E. W., Cohen A. Antagonistic effects of calcium ionophores and phorbol esters on T cell receptor mRNA levels in human thymocytes. J Immunol. 1988 Jan 15;140(2):361–366. [PubMed] [Google Scholar]
  24. Meuer S. C., Meyer zum Büschenfelde K. H. T cell receptor triggering induces responsiveness to interleukin 1 and interleukin 2 but does not lead to T cell proliferation. J Immunol. 1986 Jun 1;136(11):4106–4112. [PubMed] [Google Scholar]
  25. Minami Y., Samelson L. E., Klausner R. D. Internalization and cycling of the T cell antigen receptor. Role of protein kinase C. J Biol Chem. 1987 Sep 25;262(27):13342–13347. [PubMed] [Google Scholar]
  26. Moingeon P., Jitsukawa S., Faure F., Troalen F., Triebel F., Graziani M., Forestier F., Bellet D., Bohuon C., Hercend T. A gamma-chain complex forms a functional receptor on cloned human lymphocytes with natural killer-like activity. Nature. 1987 Feb 19;325(6106):723–726. doi: 10.1038/325723a0. [DOI] [PubMed] [Google Scholar]
  27. Paillard F., Sterkers G., Bismuth G., Gomard E., Vaquero C. Lymphokine mRNA and T cell multireceptor mRNA of the Ig super gene family are reciprocally modulated during human T cell activation. Eur J Immunol. 1988 Oct;18(10):1643–1646. doi: 10.1002/eji.1830181028. [DOI] [PubMed] [Google Scholar]
  28. Reinherz E. L., Meuer S., Fitzgerald K. A., Hussey R. E., Levine H., Schlossman S. F. Antigen recognition by human T lymphocytes is linked to surface expression of the T3 molecular complex. Cell. 1982 Oct;30(3):735–743. doi: 10.1016/0092-8674(82)90278-1. [DOI] [PubMed] [Google Scholar]
  29. Rogozinski L., Bass A., Glickman E., Talle M. A., Goldstein G., Wang J., Chess L., Thomas Y. The T4 surface antigen is involved in the induction of helper function. J Immunol. 1984 Feb;132(2):735–739. [PubMed] [Google Scholar]
  30. Royer H. D., Reinherz E. L. Multiple nuclear proteins bind upstream sequences in the promotor region of a T-cell receptor beta-chain variable-region gene: evidence for tissue specificity. Proc Natl Acad Sci U S A. 1987 Jan;84(1):232–236. doi: 10.1073/pnas.84.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Saito H., Kranz D. M., Takagaki Y., Hayday A. C., Eisen H. N., Tonegawa S. Complete primary structure of a heterodimeric T-cell receptor deduced from cDNA sequences. 1984 Jun 28-Jul 4Nature. 309(5971):757–762. doi: 10.1038/309757a0. [DOI] [PubMed] [Google Scholar]
  32. Saizawa K., Rojo J., Janeway C. A., Jr Evidence for a physical association of CD4 and the CD3:alpha:beta T-cell receptor. Nature. 1987 Jul 16;328(6127):260–263. doi: 10.1038/328260a0. [DOI] [PubMed] [Google Scholar]
  33. Sayre P. H., Chang H. C., Hussey R. E., Brown N. R., Richardson N. E., Spagnoli G., Clayton L. K., Reinherz E. L. Molecular cloning and expression of T11 cDNAs reveal a receptor-like structure on human T lymphocytes. Proc Natl Acad Sci U S A. 1987 May;84(9):2941–2945. doi: 10.1073/pnas.84.9.2941. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Shackelford D. A., Smith A. V., Trowbridge I. S. Changes in gene expression induced by a phorbol diester: expression of IL 2 receptor, T3, and T cell antigen receptor. J Immunol. 1987 Jan 15;138(2):613–619. [PubMed] [Google Scholar]
  35. Spolski R., Miescher G., Erard F., Risser R., MacDonald H. R., Mak T. W. Regulation of expression of T cell gamma chain, L3T4 and Ly-2 messages in Abelson/Moloney virus-transformed T cell lines. Eur J Immunol. 1988 Feb;18(2):295–300. doi: 10.1002/eji.1830180218. [DOI] [PubMed] [Google Scholar]
  36. Takada S., Engleman E. G. Evidence for an association between CD8 molecules and the T cell receptor complex on cytotoxic T cells. J Immunol. 1987 Nov 15;139(10):3231–3235. [PubMed] [Google Scholar]
  37. Van Wauwe J. P., De Mey J. R., Goossens J. G. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol. 1980 Jun;124(6):2708–2713. [PubMed] [Google Scholar]
  38. Vaquero C., Sanceau J., Sondermeyer P., Falcoff R. Kinetics of messenger accumulation coding for IFN gamma, related to modifications in the poly(A) RNA population of activated human lymphocytes. Nucleic Acids Res. 1984 Mar 26;12(6):2629–2640. doi: 10.1093/nar/12.6.2629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Vaquero C., Sancéau J., Catinot L., Andreu G., Falcoff E., Falcoff R. Translation of mRNA from phytohemagglutinin-stimulated human lymphocytes: characterization of interferon mRNAs. J Interferon Res. 1982;2(2):217–228. doi: 10.1089/jir.1982.2.217. [DOI] [PubMed] [Google Scholar]
  40. Veillette A., Bookman M. A., Horak E. M., Samelson L. E., Bolen J. B. Signal transduction through the CD4 receptor involves the activation of the internal membrane tyrosine-protein kinase p56lck. Nature. 1989 Mar 16;338(6212):257–259. doi: 10.1038/338257a0. [DOI] [PubMed] [Google Scholar]
  41. Weber B., Horiguchi J., Luebbers R., Sherman M., Kufe D. Posttranscriptional stabilization of c-fms mRNA by a labile protein during human monocytic differentiation. Mol Cell Biol. 1989 Feb;9(2):769–775. doi: 10.1128/mcb.9.2.769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Weyand C. M., Goronzy J., Fathman C. G. Modulation of CD4 by antigenic activation. J Immunol. 1987 Mar 1;138(5):1351–1354. [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES