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.
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| Hsu, Hui-Chen; Wu, Yalei; Mountz, John D (2006) Tumor necrosis factor ligand-receptor superfamily and arthritis. Curr Dir Autoimmun 9:37-54 |
| Musani, Solomon K; Zhang, Huang-Ge; Hsu, Hui-Chen et al. (2006) Principal component analysis of quantitative trait loci for immune response to adenovirus in mice. Hereditas 143:189-97 |
| Hsu, Hui-Chen; Scott, Donald K; Zhang, Pili et al. (2006) CD8 T-cell immune phenotype of successful aging. Mech Ageing Dev 127:231-9 |
| Zhang, Huang-Ge; Wang, Jianhua; Yang, Xinwen et al. (2004) Regulation of apoptosis proteins in cancer cells by ubiquitin. Oncogene 23:2009-15 |
| Hsu, Hui-Chen; Zhou, Tong; Mountz, John D (2004) Nur77 family of nuclear hormone receptors. Curr Drug Targets Inflamm Allergy 3:413-23 |
| Xu, X; Zhang, H-G; Liu, Z-Y et al. (2004) Defective clearance of adenovirus in IRF-1 mice associated with defects in NK and T cells but not macrophages. Scand J Immunol 60:89-99 |
| Zhang, Huang-Ge; Hyde, Karren; Page, Grier P et al. (2004) Novel tumor necrosis factor alpha-regulated genes in rheumatoid arthritis. Arthritis Rheum 50:420-31 |
| Yang, Dongyan; Zakharkin, Stanislav O; Page, Grier P et al. (2004) Applications of Bayesian statistical methods in microarray data analysis. Am J Pharmacogenomics 4:53-62 |
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