title: 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.
abstract: Intravenous injection of a bacterial superantigen such as Staphylococcus aureus enterotoxin B (SEB) causes transient activation and expansion of SEB-reactive V beta 8+ T cells, as well as specific down-regulation of the immune response, through partial deletion of superantigen-reactive T cells. Here we demonstrate that co-administration of pertussis toxin (PTX) and SEB reduces the SEB-induced deletion of V beta 8+ T cells, although it does not affect T cell activation and proliferation. PTX abrogates the SEB-driven deletion of V beta 8+CD4+ (not V beta 8+CD8+) splenocytes that is observed early (12-24 h) after SEB injection. Moreover, it antagonizes the late (> or = 4 days) deletion of V beta 8+CD4+ and V beta 8+CD8+ peripheral T cells that follows transient expansion of such cells. This phenomenon is associated with significant reductions in apoptosis and endonucleolysis and is not caused by a compensatory increase in proliferation of SEB-reactive T cells, as we determined by using a combined fluorometric analysis of cell cycle and DNA alterations, which are associated with programmed cell death. These effects are also observed in thymectomized animals, thus excluding the possibility that PTX might act by enhancing the maturation and export of thymic T cells to the periphery. Moreover, the SEB-induced reduction of V beta 8+ splenocytes is antagonized by PTX in vitro. The capacity of PTX to reduce clonal deletion depends critically on its ADP-ribosyltransferase activity, inasmuch as a non-enzymatic PTX mutant fails to act in this biologic system. We conclude that PTX selectively antagonizes or impedes the delivery of negative signals to T cells, which are stimulated by superantigens, without interfering with the transmission of stimulatory signals.
authors.affiliation: National Center of Biotechnology, CSIC, Autónoma University of Madrid, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Gonzalo
authors.forename: A
authors.initials: A
authors.lastname: González-García
authors.forename: E
authors.initials: E
authors.lastname: Baixeras
authors.forename: N
authors.initials: N
authors.lastname: Zamzami
authors.forename: R
authors.initials: R
authors.lastname: Tarazona
authors.forename: R
authors.initials: R
authors.lastname: Rappuoli
authors.forename: C
authors.initials: C
authors.lastname: Martínez
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
authors.forename: R
authors.initials: R
authors.lastname: Tarazona
authors.forename: R
authors.initials: R
authors.lastname: Terezone
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D017637:Clonal Deletion / Q000187:drug effects* / Q000502:physiology; D004768:Enterotoxins / Q000008:administration & dosage; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D037342:Pertussis Toxin; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
chemical_list: D004768:Enterotoxins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D010566:Virulence Factors, Bordetella; C031818:enterotoxin B, staphylococcal; D011065:Poly(ADP-ribose) Polymerases; D037342:Pertussis Toxin