DIFFERENTIAL T-CELL SIGNALING INDUCED BY ANTAGONIST PEPTIDE-MHC COMPLEXES AND THE ASSOCIATED PHENOTYPIC RESPONSES

Certain changes in TCR contact residues have been shown to have profou nd effects on the capacity of a peptide Ag to stimulate a T cell respo nse. Although some of these changes apparently lead to a complete loss of the ability to interact with the TCR, others result in partial ago nist activity (e.g., cytokine production without proliferation) or ant agonist activity (i.e., the capacity to inhibit the engagement to the TCR by Ag). We show MHC class II-restricted antagonist activity was as sociated with a differential pattern of early tyrosine phosphorylation events that was characterized by a preponderance of phosphorylation o f low molecular mass TCR zeta and the failure to phosphorylate Zap-70. These early tyrosine phosphorylation patterns are the same as those p reviously described for partial agonists. Thus, a partial agonist phen otype such as anergy induction cannot be ascribed in a causal manner t o this pattern of tyrosine phosphorylation. We further extend the stud ies of signal transduction elicited by agonist and antagonist peptides by characterizing differential recruitment of Zap-70 associated with TCR zeta isoforms and differential phosphorylation of p120 proto-oncog ene c-Cbl. Another early event following TCR engagement by Ag, down-mo dulation of the TCR, was studied with antagonist peptides. We show tha t antagonist peptides do not cause TCR down-modulation. This failure m ay represent a mechanism by which antagonists inhibit antigen-mediated stimulation of T cells.