title: Fas ligand-mediated cytotoxicity is directly responsible for apoptosis of normal CD4+ T cells responding to a bacterial superantigen.
abstract: Exposure of naive CD4+ T lymphocytes to superantigens such as staphylococcal enterotoxin B (SEB) induces a strong proliferative response. Prolonged exposure or subsequent restimulation of the responding T cell population with SEB leads to the apoptotic events of activation-induced cell death (AICD). However, T cells derived from either Fas-deficient lpr or Fas ligand-deficient gld autoimmune mouse strains, fail to undergo AICD under these conditions. Instead, these autoimmune T cells mount a vigorous proliferative response, suggesting a critical role for Fas/FasL interactions in this form of autoapoptosis. In the current study, we found that SEB-induced AICD was tied to the rapid induction of FasL expression in cells constitutively expressing high levels of Fas. Furthermore, the addition of soluble Fas-IgG fusion protein to the SEB-restimulated cultures blocked AICD and resulted in a 2 degrees proliferative response that was comparable in magnitude and kinetics to that of the lpr and gld T cells. The rapid onset of apoptosis in normal T cells subsequent to restimulation with SEB was in direct contrast to the proliferative response of the initial cultures, even though comparable levels of Fas and FasL RNA were found in T cells after 1 degree and 2 degrees challenge. The clonal expansion of the normal T cells responding to the initial SEB stimulation was, however, dramatically compromised when the normal cells were cocultured with an MRL-lpr responder population; addition of soluble Fas-IgG rescued the normal component of the response. Together, these data demonstrate first, that Fas/FasL interactions are intimately tied to superantigen-induced AICD, a form of autocrine cell death, and second, that FasL-mediated cytotoxicity is responsible for the disappearance of normal CD4+ T cells in lpr cocultures.
authors.affiliation: Department of Pathology and Laboratory Medicine, Boston University School of Medicine, MA 02118, USA.
authors.forename: R
authors.initials: R
authors.lastname: Ettinger
authors.forename: D J
authors.initials: DJ
authors.lastname: Panka
authors.forename: J K
authors.initials: JK
authors.lastname: Wang
authors.forename: B Z
authors.initials: BZ
authors.lastname: Stanger
authors.forename: S T
authors.initials: ST
authors.lastname: Ju
authors.forename: A
authors.initials: A
authors.lastname: Marshak-Rothstein
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology; D017209:Apoptosis / Q000276:immunology*; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004768:Enterotoxins / Q000276:immunology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D018089:Superantigens / Q000276:immunology*; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor
chemical_list: D000954:Antigens, Surface; D017252:CD3 Complex; D004768:Enterotoxins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D018089:Superantigens; D019014:fas Receptor; C031818:enterotoxin B, staphylococcal