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Recent studies demonstrated that antigen analogs can act as powerful and specific inhibitors of T cell activation, leading to the formulation of the concept that antigen analog/MHC complexes may act as antagonists of the T cell receptor (TCR). TCR antagonism appears to be associated with engagement of the TCR below a crucial affinity threshold necessary for full T cell activation. Studies addressing the molecular mechanism of this effect suggest that TCR antagonists could act by interfering with membrane-related events (such as proper receptor clustering) that might precede intracellular signaling. Discovery of the TCR antagonism phenomenon also suggested a possible rational approach to antigen-specific immunointervention in allergies and autoimmune diseases. The feasibility of such an approach is now being actively investigated. Finally, TCR antagonist peptides may provide a useful tool to probe TCR-peptide/MHC interactions involved in the process of thymic education.

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Antigen-induced activation of T cells can be specifically inhibited by antigen analogs that have been termed T-cell receptor peptide antagonists. These antagonists appear to act by inducing the formation of nonstimulatory or partially stimulatory complexes between T-cell receptors and the major histocompatibility complex molecules presenting the peptides.Herein, we have investigated the effect of T-cell receptor peptide antagonists on thymocyte negative selection. First, peptide antagonists were identified for the cytochrome c-specific T-cell clone AD1O. These peptides were then tested for their ability to induce negative selection in an in vitro model system using thymocytes from mice transgenic for the AD1O T-cell receptor. Though unable to induce mature T-cell activation, the T-cell receptor peptide antagonists induced deletion of CD4+ CD8+ thymocytes. These results suggest that negative selection of CD4+ CD8+ thymocytes can be induced by T-cell receptor interactions of a lower affinity than those required for mature T-cell activation.Mature T cells are activated to proliferate and secrete lymphokines by antigenic peptides bound to major histocompatibility complex (MHC) proteins. It has been shown recently that mature T-cell activation can be blocked by antigen analogs that are substituted at sites that contact the T-cell receptor for antigen (TCR) (1)(2)(3)(4)(5). These antigen analogs block T-cell activation at least 20-fold more efficiently than do unrelated peptides that still bind MHC proteins but have no specificity for the TCR (1). Thus, it has been proposed that these analogs act as TCR antagonists by forming an inactive complex between the TCR and the MHC protein presenting the peptide (1, 2). The mechanism by which TCR antagonists block T-cell activation is unknown. Ruppert et al. (6) found that TCR peptide antagonists do not block T cell-antigenpresenting cell (APC) conjugate formation. Instead, the antagonistic peptides blocked antigen-induced increases in phosphatidylinositol breakdown and calcium in the T cells. Thus, the TCR antagonists may act by blocking early transmembrane signaling events. Alternatively, antigen analogs that partially activate T cells may act by impeding delivery of required costimulatory signals from the APC to the T cell (4, 5).The effect of antigen analogs on T-cell maturation in the thymus has not been explored. Thymocyte development is frequently analyzed by following surface expression of the TCR and the CD4 and CD8 accessory proteins. Early thymocyte immigrants are CD4-CD8-and also lack expression of the TCR. These double negative (DN) cells then proceed to a CD4+ CD8+ [double positive (DP)] stage, where they begin to express the TCR (7,8). It is at this stage that thymocytes can undergo negative selection due to interaction with self-antigen or positive selection to become mature T cells (reviewed in ref. 9). Positive selection is mediated, in part, by an interaction of the TCR with MHC molecules on epithelial cells ofthe thymic stroma. This interaction ind...

The outcome of TCR engagement with peptide-MHC is of central importance for the immune response of the host. TCR antagonism is one phenomenon known which is characterized by selective inhibition of T cell responses by non-stimulatory antigen analogs. T cell anergy is another state resulting in T cell unresponsiveness, generally characterized by lack of proliferation and lymphokine production. In the present study, the relationship between TCR antagonism and T cell anergy was examined by using protocols known to induce either phenomenon. Re-isolation experiments demonstrated that antagonized T cells were not tolerized, in that they were fully capable of responding to a subsequent antigen challenge. Conversely, while high doses of soluble antigen could efficiently induce T cell tolerance, TCR antagonists, either alone or in conjunction with suboptimal antigen doses, could not. Taken together, these data demonstrate that TCR antagonism and T cell tolerance are phenomena independent of each other.