Age-related impairments in TCR/CD3 activation of ZAP-70 are associated with reduced tyrosine phosphorylations of zeta-chains and p59(fyn)/p56(lck) inhuman T cells

The expression and catalytic activity of the protein tyrosine kinase (PTK) ZAP-70 are needed for normal intracellular signaling through the T-cell rec eptor (TCR)/CD3 complex. However, the possible effect of aging on the catal ytic activity of ZAP-70 in human peripheral blood T cells stimulated via th e TCR/CD3 complex is unknown. The current studies show that T cells from a substantial proportion of elderly humans (12) exhibit significant reduction s in the catalytic activity, but not expression of ZAP-70 when stimulated b y ligation of the TCR/CD3 with cross-linked anti-CD3 epsilon monoclonal ant ibody OKT3. In addition, the reduced catalytic activity of ZAP-70 in T cell s from elderly subjects was not restored to the normal levels in response t o ligation of CD4 receptors, suggesting defects in PTKs linked to both CD3 and CD4 receptors. Other experiments demonstrated that the age-related impa irments of ZAP-70 activation in anti-CD3-stimulated T cells were accompanie d by decreased tyrosine phosphorylations of zeta-chains and autophosphoryla tions of the PTKs p56(lck)/p59(fyn). Moreover, the age-related defects in t hese early TCR/CD3-mediated phosphorylation events were readily detectable in both CD45RO(+) memory and CD45RA(+) naive T cells. Thus, these results s uggest that defects in early TCR/CD3-mediated phosphorylation events among CD45RO(+) memory and CD45RA+ naive T cells from certain elderly humans may contribute to impaired induction of ZAP-70 catalytic activity. (C) 1999 Els evier Science Ireland Ltd. All rights reserved.