Exogenous superantigens acutely trigger distinct levels of peripheral T cell tolerance/immunosuppression: dose-response relationship.
Ligand-specific immunosuppression requires an understanding of the parameters that control peripheral T cell tolerance. T cell receptor (TcR) transgenic mice offer a clear advantage for studying post-thymic tolerance mechanisms in vivo that are operational in a monoclonal T cell population with preselected antigen specificity. Yet it is unclear whether the rules defined in monoclonal T cells of genetically manipulated mice reflect those operative in clonally diverse peripheral T cells of normal mice. To analyze acute tolerance mechanisms in unselected peripheral T cells, we challenged normal mice with the superantigen staphylococcal enterotoxin B (SEB) and analyzed ligand-reactive V beta 8+ T cells for TcR-triggered tolerance mechanisms such as anergy, TcR down-regulation, or apoptosis. Upon challenge with graded doses of SEB (0.001-10 micrograms) V beta 8+ T cells become anergic within 6-16 h. Importantly, a dosage effect of SEB in regard to the level of anergy induced was observed. Anergy induced by low concentrations of SEB (0.001-0.1 microgram) is transient and is overcome by clonal growth, while higher concentrations of SEB (0.1-10 micrograms) cause long-lasting anergy resistant to cell cycle progression. At high SEB concentrations (1-10 mg) about 50% of the anergic V beta 8+ T cells additionally down-regulate their TcR-CD3 complex, followed by a loss of CD2, CD4, CD8 accessory molecules. In parallel, T cell phenotype-negative but genotypically V beta 8+ T cells are generated. The T cell phenotype-negative cells reacquire their V beta 8+ T cell phenotype upon culture in vitro. In vivo, a subset of V beta 8+ cells, defined by an intermediate stage of TcR down-regulation, i.e. V beta 8lowCD3+ cells, but not T cell phenotype-negative cells are selectively programmed for apoptosis, which occurs within 1 h. These data suggest that SEB triggers distinct tolerance pathways which operate in a hierarchical fashion in clonally diverse ligand-reactive T cells. Specifically, the results illustrate the power of exogenous superantigens to exploit these distinct tolerance pathways, thereby achieving distinct levels of immunosuppression.
Miethke
T
T
Institute of Medical Microbiology and Hygiene, Technical University of Munich.
Wahl
C
C
Gaus
H
H
Heeg
K
K
Wagner
H
H
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001483:Base Sequence; D017252:CD3 Complex / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D015536:Down-Regulation; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D008198:Lymph Nodes / Q000166:cytology; D051379:Mice; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000276:immunology; D016133:Polymerase Chain Reaction; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D017252:CD3 Complex; D004768:Enterotoxins; D009707:Nucleosomes; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C031818:enterotoxin B, staphylococcal