TRANSIENT ALTERATION OF T-CELL FINE SPECIFICITY BY A STRONG PRIMARY STIMULUS CORRELATES WITH T-CELL RECEPTOR DOWN-REGULATION

P14 mice expressing a transgenic TCR specific for the lymphocytic chor iomeningitis virus glycoprotein p33 epitope were used to study the ind uction of CTL effector activity by a variety of ligands. Surprisingly, p33 variants which are weaker agonists for the P14 TCR than the wild- type p33 peptide were able to induce more potent effecters with a broa der range of cytolytic specificity. Similarly, low concentrations of p 33 were more effective than higher concentrations. These results corre lated with no or only moderate TCR down-regulation by variants of p33 and low p33 concentrations. This phenotype observed after 18h of cultu re was transient as progressive restoration of reactivity was observed at 42 or 66 h in the cultures stimulated with high p33 concentrations and this correlated with recovery of TCR surface levels. TCR down-reg ulation was blocked by src family kinase inhibitors. These findings in dicate that the specificity of a T cell can be fine-tuned by the natur e of the primary stimulus correlating with surface TCR revel and imply an important role for src family kinases in the differential regulati on of surface TCR levels upon TCR engagement by different ligand/MHC c omplexes.