Altered peptide ligands induce quantitatively but not qualitatively different intracellular signals in primary thymocytes.

Interaction of the T cell receptor (TCR) with peptide/major histocompatibility complexes (MHC) in the thymus is of critical importance for developing thymocytes. In a previous study, we described an antagonist peptide that inhibited negative selection of transgenic thymocytes induced by an agonist peptide. In this study we show that this antagonist peptide can induce positive selection of CD8(+) thymocytes more efficiently than the agonist or the weak agonist peptides, whereas the opposite is true for their ability to cause negative selection. The intracellular signals induced in thymocytes by such peptides after TCR ligation was examined in CD4(+)8(+) double-positive thymocytes from F5/beta2mo/Rag-1(o) transgenic mice. TCR ligation with either the agonist, weak agonist, or antagonist peptide variants resulted in hyperphosphorylation of CD3zeta, CD3epsilon, ZAP-70, Syk, Vav, SLP-76, and pp36-38. The extent of phosphorylation of these intracellular proteins correlated with the efficiency with which the peptide analogs induced apoptosis of immature thymocytes. Unexpectedly, there was no correlation between the upstream TCR signaling pathways analyzed and the capacity of the different peptides to induce positive selection.