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 tymphocytes 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 p56lck 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 p59fyn did not show changes with aging, suggesting that p59fyn did not compensate for the decreased activity of p56lck. We also found that the extent of tyrosine phosphorylation of the adaptor protein p95vav was similar in activated T lymphocytes 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 p56lck and ZAP-70. Impairment in the activities of these twokey components of T cell signaling may contribute to reduced immune functions associated with aging.
Fülöp
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T
Centre de Recherche en Gérontologie et Gériatrie, Institut Universitaire de Gériatrie de Sherbrooke, Québec, Canada. tfulop@courrier.usherb.ca
Gagné
D
D
Goulet
A C
AC
Desgeorges
S
S
Lacombe
G
G
Arcand
M
M
Dupuis
G
G
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000276:immunology* / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism*; D018797:Cell Cycle Proteins; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D008297:Male; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology*; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
D017252:CD3 Complex; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496618:VAV1 protein, human; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C494957:FYN protein, human; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human