EXOGENOUS SUPERANTIGENS ACUTELY TRIGGER DISTINCT LEVELS OF PERIPHERALT-CELL TOLERANCE IMMUNOSUPPRESSION - DOSE-RESPONSE RELATIONSHIP/

Ligand-specific immunosuppression requires an understanding of the par ameters that control peripheral T cell tolerance. T cell receptor (TcR ) transgenic mice offer a clear advantage for studying post-thymic tol erance mechanisms in vivo that are operational in a monoclonal T cell population with preselected antigen specificity. Yet it is unclear whe ther the rules defined in monoclonal T cells of genetically manipulate d mice reflect those operative in clonally diverse peripheral T cells of normal mice. To analyze acute tolerance mechanisms in unselected pe ripheral T cells, we challenged normal mice with the superantigen stap hylococcal enterotoxin B (SEB) and analyzed ligand-reactive V beta 8() T cells for TcR-triggered tolerance mechanisms such as anergy, TcR d own-regulation, or apoptosis. Upon challenge with graded doses of SEB (0.001-10 mu g) V beta 8(+) T cells become anergic within 6-16 h. Impo rtantly, a dosage effect of SEB in regard to the level of anergy induc ed was observed. Anergy induced by low concentrations of SEB (0.001-0. 1 mu g) is transient and is overcome by clonal growth,while higher con centrations of SEB (0.1-10 mu g) cause long-lasting anergy resistant t o cell cycle progression. At high SEB concentrations (1-10 mg) about 5 0% of the anergic V beta 8(+) T cells additionally down-regulate their TcR-CD3 complex, followed by a loss of CD2, CD4, CD8 accessory molecu les. In parallel, T cell phenotype-negative but genotypically V beta 8 (+) T cells are generated. The T cell phenotype-negative cells reacqui re 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 8(low)CD3(+) cells, but not T cell pheno type-negative cells are selectively programmed for apoptosis, which oc curs within 1 h. These data suggest that SEB triggers distinct toleran ce pathways which operate in a hierarchical fashion in clonally divers e ligand-reactive T cells. Specifically, the results illustrate the po wer of exogenous superantigens to exploit these distinct tolerance pat hways, thereby achieving distinct levels of immunosuppression.