Impaired apoptosis and immune senescence - cause or effect?
Aged animals and humans exhibit a decreased T-cell activation response although they also exhibit increased susceptibility to responses to self-antigens and a loss of self-tolerance. The age-related alteration in T-cell reactivity, polyclonal expansion of T cells, and enhanced production of autoantibodies may reflect the numerous age-associated alterations in the T-cell arm of the immune system that have been revealed in numerous studies. These studies suggest that subpopulations of T cells are not deleted appropriately in older animals. They further suggest that an age-related impairment of Fas/Fas ligand (FasL)-mediated apoptosis - which plays a major role in activation-induced cell death (AICD) of T cells - may contribute to compromised regulation of the immune system. The likely mechanisms that may lead to impaired induction of FasL in AICD senescent T cells include an age-related shift from the apoptosis-sensitive T-helper 1 cell (Th1) response to the AICD-resistant Th2 response, aberrant T-cell receptor/CD3 downstream-signaling pathways, and altered CD28/B7-mediated T-cell costimulatory signals. Pathologically, accumulation of AICD-senescent T cells is associated with a defective cytotoxic T lymphocyte response and generation of autoreactive T cells. Based on the accumulating evidence, we propose that the emergence of the FasL(lo) AICD-senescent T cells is not only an effect of immune aging but also an important cause of T-cell proliferative senescence in both humans and mice.
Hsu
Hui-Chen
HC
Department of Medicine, Division of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, 35294, USA.
Scott
Donald K
DK
Mountz
John D
JD
D000375:Aging / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis; D053222:Fas Ligand Protein; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism / Q000821:virology
D015703:Antigens, CD; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins