DEFECTIVE FAS APOPTOSIS DURING AGING

University Of Alabama At Birmingham, Birmingham AL

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Abstract

APPLICANT'S DESCRIPTION: The goal of the present proposal is to determine if T cells acquire defects in activation-induced cell death (AICD) prior to development of replicative senescent. This proposal will also determine whether transfer of these T cells can induce the development of autoimmune disease in recipient young mice. Fas/FasL-mediated AICD is an important mechanism for the maintenance of immune tolerance by removal of autoreactive T cells. There is, however, an increased population of T cells from aged mice that is resistant to AICD after in vitro cell activation and after transfer in vivo into young recipient severe-combined immune deficiency (SCID) mice. The AICD-resistant pre-senescent T cells, unlike the replicative senescent cells, exhibit a delayed but equivalent capability to undergo cell cycle as that from young mice. The central hypothesis of the present proposal is that repeated stimulation of T cells will drive T cells into an apoptosis resistant state prior to the occurrence of replicative senescence, and that transfer of these pre-senescent T cells, but not replicative senescent T cells, into SCID mice will lead to the development of autoimmune disease. The first goal will be to determine if the AICD dysfunction is correlated with the development of pre-senescent T cells. The second goal will be to determine if the AICD dysfunction is due to a defect in Fas ligand or Fas apoptosis signaling. The third goal will be to determine if in vivo transfer of apoptosis-resistant and pre-senescent T cells into SCID mice can induce the development of autoimmune disease. The fourth goal will be to determine if correction of the Fas mediated AICD defect in T cells by transfer of the pro-apoptotic FasL gene into these cells may delay the onset of pre-senescent T cells and prevent the development of autoimmune T cells after transfer into SCID mice. The data and concepts presented in this application represent a paradigm shift in our understanding of the aging immune system and clarify some of the current controversy concerning the functional status of aging T cells. The completion of proposed experiments will yield new information of the molecular and cellular mechanisms of defective apoptosis leading to T-cell senescence and provide novel strategies to delay or correction of T-cell senescence by modulation of apoptosis.