Excessive apoptosis of mature T lymphocytes is a characteristic feature of human immune senescence

Abstract

Recent evidence suggests that apoptotic deletion of activated mature lymphocytes is an essential physiological process implicated in both the regulation of the immune response and the control of the overall number of immunocompetent cells. Tightly interrelated signaling mechanisms convey either activation or death messages, achieving the necessary equilibrium between cell proliferation and cell deletion. During the course of aging, numerous alterations of these signaling pathways may shift the balance toward cell death. In the present investigation, the reduced DNA synthesis of anti-CD3 activated T lymphocytes isolated from elderly individuals is associated with an important and early cell deletion from the cultures. Visualization of DNA fragmentation in the remaining activated cells argues in favour of the apoptotic nature of the cell deletion. Quantification of histone-associated DNA fragments shows that the apoptotic process is greatly amplified in activated lymphocytes derived from senescent organisms. Further analysis reveals that IL-2 deprivation does not play a significant role in the age-related increase in apoptosis. Partial correction of this excessive apoptosis by products that bypass the early steps of the signaling cascade suggests that transmembrane signaling defects are involved in this process. Exploration of the antioxidant pathway reveals that the increased susceptibility of lymphocytes from senescent organisms to apoptosis is not explained by a decreased Bcl-2 expression and is not influenced by a modification of the intracellular concentration of glutathione (GSH).