Increased Zap-70 association with CD3zeta in CD4 T cells from old mice

Aging diminishes the amount of phosphotyrosine in the CD3zeta chains of resting and activated mouse CD4 T cells by about threefold and might therefore be expected to a corresponding decline in Zap-70 association with CD3zeta and in Zap-70 kinase function in CD3zeta complexes. We show here that aging leads, unexpectedly, to an approximately twofold increase in the amount of Zap-70 associated with CD3zeta in resting CD4 T cells. There is, however, no effect of age on total intracellular Zap-70 content. Cross-linking CD3 to CD4 leads to an increase of only 50% in the functional activity of Zap-70 in CD3zeta complexes from freshly isolated CD4 T cells of young donors. Compared to Jurkat and HT-2 cells, fresh T cells show both higher baseline levels and lower induced levels of Zap-70 function in CD3zeta complexes. CD4 T cells from old mice have baseline levels of Zap-70 activity similar to those seen in activated T cells from young mice, and these levels do not increase after CD3/CD4 cross-linking. Tyrosine-specific phosphorylation of Zap-70 is also higher at rest in old T cells than in young T cells and inducible only in cells from young donors. These data suggest that age-related defects in T cell activation are not likely to be attributable simply to a decline in Zap-70 association with CD3zeta or to diminished Zap-70 phosphorylation. The increase with age in CD3zeta-Zap association, despite the loss with age in CD3zeta tyrosine phosphorylation, suggests that the pattern of tyrosine phosphate groups among CD3zeta ITAM groups may be different in T cells from young and old donors or that access to ITAM regions within CD3zeta may be blocked by inter- or intramolecular steric hindrance in young CD4 T cells.