Costimulation of aged human naive T cells through ICAM-1

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In response to PAR-03-056, this proposal responds to topics: #5, Vaccine Development and #18, Functional Senescence. Diminished immune responsiveness in aging individuals limits their ability to combat infectious agents and also decreases the effectiveness of vaccines designed to promote generation of effector and memory cells from the naive T cell population. It is imperative to examine all methods by which the immune system might be modulated in aging individuals. We will examine effects of second signal strategies on the aging T cell immune response. Movement of halve T cells to effector and ultimately to memory cells depends on receipt of two signals at the cell surface: (1) an antigen-specific interaction of the T cell antigen receptor with antigen in the context of MHC on the surface of an antigen-presenting cell; and (2) an antigen-independent second signal delivered by a cell surface protein. The best-studied 2nd signal receiver is CD28, although several T cell surface proteins can receive 2nd signals. We recently published that stimulation through ICAM-1 on a T cell can deliver a 2nd signal capable of activating the CD4+ T cell to assume properties of effector cells of primarily the Th1 subset. Thus far, only costimulation through CD28 has been shown capable of moving nafve T cells all the way to memory cells, and these include both Th1 and Th2 cells. We have just submitted a paper demonstrating that costimulation through ICAM-1 can move CD4+ nafve T cells to memory cells representing only Thl cells. Thus, only two potential 2nd signals are capable of memory induction. ICAM-1 has not been tested in any capacity for ability to activate T cells from aging individuals and it is possible that stimulation through ICAM-1 can enhance responsiveness of aging T cells. In the present Re3 proposal, we will investigate the ability of costimulation through ICAM-1: (1) to activate nalve T cells taken from aging individuals and (2) to move na'fve T cells from aging individuals to effector and then to memory cells. These two aims will prepare us for our long-term project, which will be to investigate the ability of stimulation through ICAM-1 to modulate immune responsiveness in aging humans and mouse models.