SummaryRecent studies have investigated how defined peptides influence T cell development. Using a T cell receptor-transgenic [32-microglobulin--deficient model, we have examined T cell maturation in fetal thymic organ cultures in the presence of various peptides containing single-alanine substitutions of the strong peptide agonist, p33. Cocultivation with the peptide A4Y, which contains an altered T cell contact residue, resulted in efficient positive selection. Several in vitro assays demonstrated that A4Y was a moderate agonist relative to p33. Although A4Y promoted positive selection over a wide concentration range, high doses of this peptide could not induce clonal deletion. Thymocytes maturing in the presence of A4Y were no longer able to respond to A4Y, but could proliferate against p33. These studies demonstrate that (a) peptides that induce eflficient positive selection at high concentrations are not exclusively antagonists; (b) some agonists do not promote clonal deletion; (c) positive selection requires a unique T cell receptor-peptide-major histocompatibility complex interaction; and (d) interactions with selecting peptides during T cell ontogeny may define the functional reactivity of mature T cells. T CRs expressed on maturing thymocytes interact withpeptide-MHC complexes on thymic stromal cells and transmit signals that lead to either positive or negative T cell selection (1-3). Positive selection is an active process that rescues self-MHC-restricted thymocytes from programmed cell death. In contrast, negative selection tolerizes potentially autoreactive T cells, either through clonal deletion or unresponsiveness. Clonal deletion physically removes thymocytes by inducing apoptosis, as compared with unresponsiveness, which modifies developing T cells so that they can no longer respond against the tolerizing antigen. Since positive and negative selection shape the TCR repertoire and define the basis of self-/non-self-antigens, much research has focused on understanding T cell development. Studies have addressed how clonotypic TCRs expressed on CD4+CD8 + double-positive thymocytes can distinguish between these two selection events. Although it has been demonstrated that peptides are involved in positive and negative selection (4, 5), it remains controversial whether the selecting ligand has a qualitative or quantitative role in determining the fate of the developing T cell.Recently, altered peptide ligands have been identified that can inhibit some or all mature T cell effector functions (6-10). Antagonist peptides are defined as ligands that engage TCRs and actively inhibit biological responses. Partial agonists are closely related peptides that stimulate a subset ofT cell effector functions (11). This is in contrast with agonist peptides, which induce a complete range ofT cell responses. Studies by Hogquist et al. (12,13) and Jameson et al. (14) showed a correlation between peptide antagonists and positive selection. These results suggest that a positively selecting peptide is qualitatively diffe...

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