ACTIVATION OF MURINE T-CELLS VIA PHOSPHOLIPASE-C-GAMMA-1-ASSOCIATED PROTEIN-TYROSINE PHOSPHORYLATION IS REDUCED WITH AGING

Cross-linking of the T-cell receptor (CD3) induces activation of tyros ine kinases and the subsequent phosphorylation of intracellular protei n substrates. We examined whether early events in signal transduction through CD3 or CD3 x CD4 receptor ligation were altered in aged murine T-lymphocytes. Both calcium mobilization and tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1) were decreased in T-lymphocy tes from old mice. In addition, there was less tyrosine phosphorylatio n of a 35/36 kDa protein both in whole cell lysates and in PLC gamma 1 immunoprecipitates from old mice. This 35/36 kDa phosphoprotein binds specifically to the SH2 domains of PLC gamma 1. Using a fusion protei n containing the SH2 domains of PLC gamma 1 and human IgG1 heavy chain , we identified three additional proteins that bind to the SH2 domains which were tyrosine phosphorylated following CD3 x CD4 ligation to a lesser degree with age. The tyrosine phosphorylation of two phosphopro teins binding to a fusion protein consisting of the SH2 domains of GAP (ras GTPase-activating protein) and human IgG1 heavy chain was also r educed with aging. The observed binding to SH2 domains was thiol redox sensitive. Thus, decreases in antioxidants with age may be responsibl e for inhibitory effects on PLC gamma 1-phosphatidylinositol signaling through redox regulation of tyrosine phosphoproteins.