Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex

Cellular immune responses decrease with aging. Lymphocytes of aged individuals do not perform as well as cells from young subjects in a number of in vitro assays including cell proliferation, cytokine production, and protection against apoptosis. Here, we have tested the hypothesis that a decrease in T cell responses in lymphocytes from elderly subjects could parallel a decrease in the activity of protein tyrosine kinases (PTK) associated with signal transduction in T lymphocytes. We report that anti-CD3-triggered T lymphocyte proliferation was significantly decreased in T lymphocytes from elderly subjects, but the decrease was not due to an alteration of the percentage or mean fluorescence intensities of CD3, CD4, and CD45. Of significance, the activities of p56(lck) and ZAP-70 in vitro were significantly decreased in T lymphocytes from elderly subjects compared to young individuals. However, the level of expression of the two kinases did not change with aging. The activity of p59(fyn) did not show changes with aging, suggesting that p59(fyn) did not compensate for the decreased activity of p56(lck). We also found that the extent of tyrosine phosphorylation of the adaptor protein p95(vav) was similar in activated Tlymphocytes from elderly and young subjects. Our results suggest that the altered cellular immune responses observed in T lymphocytes with aging may be the result, at least in part, of an alteration in early events associated with signal transduction through the TcR/CD3 complex that translates into decreased activities of p56(lck) and ZAP-70. Impairment in the activities of these two key components of T cell signaling may contribute to reduced immune functions associated with aging. (C) 1999 Elsevier Science Inc. All rights reserved.