Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Sep 1;180(3):1147–1152. doi: 10.1084/jem.180.3.1147

Pertussis toxin inhibits activation-induced cell death of human thymocytes, pre-B leukemia cells and monocytes

PMCID: PMC2191663  PMID: 8064231

Abstract

Activation of human thymocytes and pre-B cells via the CD3/T cell receptor (TCR) complex or the IgM/B cell receptor complex, respectively, results in apoptotic cell death. Similarly, cross-linking of the activation marker CD69, which belongs to the natural killer complex, causes apoptosis of lipopolysaccharide-preactivated monocytes. Here we show that pertussis toxin (PTX) inhibits the activation-induced apoptosis of these three cell types, though it fails to prevent the programmed cell death that follows exposure of cells to the synthetic glucocorticoid dexamethasone (thymocytes, pre-B cells) or to interleukin 4 (monocytes). The capacity of pertussis toxin to suppress activation-induced death is not due to quenching of the activation signal, because thymocytes exposed to PTX are still capable of mobilizing Ca2+ after TCR-alpha/beta cross-linking and proliferate in response to costimulation with PTX and CD3/TCR ligation. The apoptosis- inhibitory effect of PTX depends on the presence of an intact adenosine diphosphate (ADP)-ribosylating moiety, since a mutant pertussis toxin molecule that lacks enzymatic activity, but still possesses the membrane translocating activity, fails to interfere with activation- induced cell death. A toxin that induces a different spectrum of ADP ribosylation than PTX, cholera toxin, fails to inhibit apoptosis. To suppress apoptosis, the intact PTX holotoxin must be added to cells before the lethal activation step; its addition 30 min after initial activation remains without effect on apoptosis. These data unravel a PTX sensitive signal transduction event that intervenes during an early step of activation-induced cell death of immune cells.

Full Text

The Full Text of this article is available as a PDF (670.6 KB).

Selected References

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

  1. Broekhuyse R. M., Kuhlmann E. D., Winkens H. J. Experimental autoimmune posterior uveitis accompanied by epitheloid cell accumulations (EAPU). A new type of experimental ocular disease induced by immunization with PEP-65, a pigment epithelial polypeptide preparation. Exp Eye Res. 1992 Dec;55(6):819–829. doi: 10.1016/0014-4835(92)90008-g. [DOI] [PubMed] [Google Scholar]
  2. Cohen J. J. Apoptosis. Immunol Today. 1993 Mar;14(3):126–130. doi: 10.1016/0167-5699(93)90214-6. [DOI] [PubMed] [Google Scholar]
  3. Gonzalo J. A., González-García A., Baixeras E., Zamzami N., Tarazona R., Rappuoli R., Martínez C., Kroemer G., Tarazona R., Terezone R. Pertussis toxin interferes with superantigen-induced deletion of peripheral T cells without affecting T cell activation in vivo. Inhibition of deletion and associated programmed cell death depends on ADP-ribosyltransferase activity. J Immunol. 1994 May 1;152(9):4291–4299. [PubMed] [Google Scholar]
  4. Goverman J., Woods A., Larson L., Weiner L. P., Hood L., Zaller D. M. Transgenic mice that express a myelin basic protein-specific T cell receptor develop spontaneous autoimmunity. Cell. 1993 Feb 26;72(4):551–560. doi: 10.1016/0092-8674(93)90074-z. [DOI] [PubMed] [Google Scholar]
  5. Groux H., Torpier G., Monté D., Mouton Y., Capron A., Ameisen J. C. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med. 1992 Feb 1;175(2):331–340. doi: 10.1084/jem.175.2.331. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Kroemer G., Martínez C. Pharmacological inhibition of programmed lymphocyte death. Immunol Today. 1994 May;15(5):235–242. doi: 10.1016/0167-5699(94)90249-6. [DOI] [PubMed] [Google Scholar]
  7. Lobet Y., Feron C., Dequesne G., Simoen E., Hauser P., Locht C. Site-specific alterations in the B oligomer that affect receptor-binding activities and mitogenicity of pertussis toxin. J Exp Med. 1993 Jan 1;177(1):79–87. doi: 10.1084/jem.177.1.79. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Lokeshwar V. B., Bourguignon L. Y. The lymphoma transmembrane glycoprotein GP85 (CD44) is a novel guanine nucleotide-binding protein which regulates GP85 (CD44)-ankyrin interaction. J Biol Chem. 1992 Nov 5;267(31):22073–22078. [PubMed] [Google Scholar]
  9. Mangan D. F., Robertson B., Wahl S. M. IL-4 enhances programmed cell death (apoptosis) in stimulated human monocytes. J Immunol. 1992 Mar 15;148(6):1812–1816. [PubMed] [Google Scholar]
  10. McConkey D. J., Orrenius S., Jondal M. Agents that elevate cAMP stimulate DNA fragmentation in thymocytes. J Immunol. 1990 Aug 15;145(4):1227–1230. [PubMed] [Google Scholar]
  11. Meyaard L., Otto S. A., Jonker R. R., Mijnster M. J., Keet R. P., Miedema F. Programmed death of T cells in HIV-1 infection. Science. 1992 Jul 10;257(5067):217–219. doi: 10.1126/science.1352911. [DOI] [PubMed] [Google Scholar]
  12. Nemoz G., Prigent A. F., Aloui R., Charpin G., Gormand F., Gallet H., Desbos A., Biot N., Perrin-Fayolle M., Lagarde M. Impaired G-proteins and cyclic nucleotide phosphodiesterase activity in T-lymphocytes from patients with sarcoidosis. Eur J Clin Invest. 1993 Jan;23(1):18–27. doi: 10.1111/j.1365-2362.1993.tb00713.x. [DOI] [PubMed] [Google Scholar]
  13. Pizza M., Covacci A., Bartoloni A., Perugini M., Nencioni L., De Magistris M. T., Villa L., Nucci D., Manetti R., Bugnoli M. Mutants of pertussis toxin suitable for vaccine development. Science. 1989 Oct 27;246(4929):497–500. doi: 10.1126/science.2683073. [DOI] [PubMed] [Google Scholar]
  14. Rosoff P. M., Mohan C. Unidirectional, heterologous desensitization of the pertussis toxin receptor by the CD3/TCR complex. J Immunol. 1992 Nov 15;149(10):3191–3199. [PubMed] [Google Scholar]
  15. Sudweeks J. D., Todd J. A., Blankenhorn E. P., Wardell B. B., Woodward S. R., Meeker N. D., Estes S. S., Teuscher C. Locus controlling Bordetella pertussis-induced histamine sensitization (Bphs), an autoimmune disease-susceptibility gene, maps distal to T-cell receptor beta-chain gene on mouse chromosome 6. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3700–3704. doi: 10.1073/pnas.90.8.3700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Uehara T., Miyawaki T., Ohta K., Tamaru Y., Yokoi T., Nakamura S., Taniguchi N. Apoptotic cell death of primed CD45RO+ T lymphocytes in Epstein-Barr virus-induced infectious mononucleosis. Blood. 1992 Jul 15;80(2):452–458. [PubMed] [Google Scholar]
  17. Witvliet M. H., Vogel M. L., Wiertz E. J., Poolman J. T. Interaction of pertussis toxin with human T lymphocytes. Infect Immun. 1992 Dec;60(12):5085–5090. doi: 10.1128/iai.60.12.5085-5090.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Ziegler S. F., Ramsdell F., Hjerrild K. A., Armitage R. J., Grabstein K. H., Hennen K. B., Farrah T., Fanslow W. C., Shevach E. M., Alderson M. R. Molecular characterization of the early activation antigen CD69: a type II membrane glycoprotein related to a family of natural killer cell activation antigens. Eur J Immunol. 1993 Jul;23(7):1643–1648. doi: 10.1002/eji.1830230737. [DOI] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES