The overall goal of this proposal is to evaluate which facets of CD4 memory generation and maintenance are compromised in aged animals and to probe the underlying causes of any defined defects. The first series of experiments compares the function of effector helper T cells derived in vitro from TCR transgenic T cells of young and old mice. After short term culture, newly generated effector T cells will be transferred into T cell deficient syngeneic hosts. The transferred cells will be assayed for their ability to home to different sites in vivo, and their ability to expand in these sites over time. Soon after transfer, the cell surface phenotype will be monitored for the appearance of cells with a memory phenotype and evidence for the induction of apoptosis and anergy. The ability to generate memory cells (6 week post-transfer) and to maintain the memory cells in vivo (12 - 16 week post-transfer) will be assessed quantitatively by flow cytometry. Proliferative activity and turnover rates will also be determined. The memory cells generated in vivo will then be re-stimulated with antigen in vitro to reveal any functional differences between the two groups of cells (from young and old). Proliferative capacity, the extent and spectrum of cytokines production and susceptibility to activation induced cell death (AICD) will be assessed. Finally, mixed transfer experiments are proposed to evaluate the effects of competition between newly generated effector cells from young and old animals on the establishment and propagation of the memory compartment in the adoptive host. The second series of experiments addresses the role of IL- 2, IFN-g type I and TNF in the generation and maintenance of CD4 memory. In a similar design to the first series, type 2 helper cells will be generated in vitro from mice lacking IL2R, IINF-g type I, TNFRI and II. While the initial experiments use polyclonal stimuli to generate the effectors for transfer, the various KO mice are being backcrossed to the AND TCR transgenic line to more closely parallel the first studies using antigen stimulus.
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| Ishimaru, Naozumi; Kishimoto, Hidehiro; Hayashi, Yoshio et al. (2006) Regulation of naive T cell function by the NF-kappaB2 pathway. Nat Immunol 7:763-72 |
| Boyman, Onur; Cho, Jae-Ho; Tan, Joyce T et al. (2006) A major histocompatibility complex class I-dependent subset of memory phenotype CD8+ cells. J Exp Med 203:1817-25 |
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| Kovar, Marek; Boyman, Onur; Shen, Xuefei et al. (2006) Direct stimulation of T cells by membrane vesicles from antigen-presenting cells. Proc Natl Acad Sci U S A 103:11671-6 |
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