Costimulation of aged human naive T cells through ICAM-1

作为对PAR-03-056的回应，本提案回应了以下主题：#5，疫苗开发和#18， 功能性衰老衰老个体中免疫应答性降低限制了其对抗感染因子的能力，并且还降低了设计用于促进从初始T细胞群体产生效应细胞和记忆细胞的疫苗的有效性。有必要检查所有的方法，通过这些方法可以调节衰老个体的免疫系统。我们将研究第二信号策略对衰老T细胞免疫应答的影响。半个T细胞向效应细胞并最终向记忆细胞的移动取决于在细胞表面接收两种信号：（1）在抗原呈递细胞表面上的MHC的背景下T细胞抗原受体与抗原的抗原特异性相互作用;和（2）由细胞表面蛋白递送的抗原非依赖性第二信号。研究最多的第二信号接收器是CD 28，尽管有几种T细胞表面蛋白可以接收第二信号。我们最近发表了通过T细胞上的ICAM-1刺激可以传递能够激活CD 4 + T细胞的第二信号，以呈现主要是Th 1亚群的效应细胞的特性。到目前为止，只有通过CD 28的共刺激才能将幼稚T细胞一直移动到记忆细胞，这些细胞包括Th 1和Th 2细胞。我们刚刚提交了一篇论文 这表明通过ICAM-1的共刺激可以将CD 4 + nafve T细胞移动到记忆细胞， 仅代表Thl细胞。因此，只有两个潜在的第二信号能够进行存储器感应。ICAM-1还没有被测试过任何激活来自衰老个体的T细胞的能力，并且通过ICAM-1的刺激可能会增强衰老T细胞的反应性。在目前的Re 3提案中，我们将研究通过ICAM-1的共刺激的能力：（1）激活取自衰老个体的nalve T细胞和（2）将来自衰老个体的幼稚T细胞移动到效应细胞，然后移动到记忆细胞。这两个目标将为我们的长期项目做好准备，该项目将研究通过ICAM-1刺激调节衰老人类和小鼠模型免疫反应的能力。

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.