Impaired apoptosis and immune senescence – cause or effect?

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Abstract
Summary:  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 FasLlo 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.