Memory T lymphocyte-mediated innate immunity

描述（由申请人提供）：记忆T细胞（Tm）以少量存在于宿主中。当再次遇到病原体时，Tm可以迅速响应以增加数量并分化成效应细胞，作为产生有效的适应性免疫的一种方式。在这个提议中，我们将研究一个新的现象，即少量的Tm细胞可以通过连接CD 137分子的刺激而选择性地扩增成大量，而无需再次暴露于抗原。更重要的是，通过CD137刺激的Tm细胞的增殖伴随着对病原体的先天免疫功能的获得。在这项提案中，我们将扩大我们的观察，以解决基本问题，这将是至关重要的未来应用的TM介导的先天免疫生物防御。待测试的中心假设是通过CD137刺激激活Tm可以诱导针对病原体感染的有效先天免疫，并且可以潜在地开发为生物防御的手段。我们将首先解决Tm介导的先天免疫的基本特征，包括由CD 137选择性激活Tm的分子基础，先天免疫的动力学和先天免疫向适应性免疫的转变，使用单核细胞增生李斯特菌（LM）作为模式病原体。我们还将在体内检验以下假设：CD 137刺激直接激活亚群Tm以产生IFN-γ和其他可溶性和细胞表面分子，导致巨噬细胞和其他效应细胞的激活以消除LM感染。此外，我们将描绘Tm介导的先天免疫的细胞和分子组成部分，以及在Tm中的CD137信号转导的信号转导事件的理解。最后，我们将扩展我们的研究结果，以确定这种方法的治疗潜力，测试CD 137刺激在消除LM，老年动物感染，免疫受损群体以及这种治疗的潜在副作用中的作用。这些研究不仅将确立CD137信号在Tm生长和功能成熟中的作用，而且还将为未来开发针对病原体的生物防御新方法奠定基础。

DESCRIPTION (provided by applicant): Memory T cells (Tm) are present in small quantities in a host. Upon re-encountering pathogens, Tm could respond rapidly to increase the number and to differentiate into effector cells as a way to generate a potent adaptive immunity. In this proposal, we will study a new phenomenon that small numbers of Tm cells could be selectively expanded into large quantities by stimulation through ligation of CD137 molecule without re- exposure to antigen. More importantly, proliferation of Tm cells by CD137 stimulation is accompanied by acquisition of innate immunity function to pathogens. In this proposal, we will extend our observation to address fundamental issues which will be critical for future application of Tm-mediated innate immunity in biodefense. A central hypothesis to be tested is that activation of Tm by CD137 stimulation could induce potent innate immunity against pathogen infection and could be developed potentially as a mean for biodefense. We will first address basic features of Tm-mediated innate immunity including molecular basis of selective activation of Tm by CD137, kinetics of innate immunity and transition of innate to adaptive immunity, using Listeria monocytogenes (LM) as a model pathogen. We will also test hypothesis in vivo that CD 137 stimulation directly activates subset Tm to produce IFN-gamma and other soluble and cell surface molecules, leading to activation of macrophages and other effector cells to eliminate LM infection. In addition, we will delineate cellular and molecular components of Tm-mediated innate immunity, as well as understanding of signal transduction events of CD137 signaling in Tm. Finally we will extend our findings to determine therapeutic potential of this method, test the role of CD137 stimulation in the elimination of LM, infection in elder animals, an immunologically compromised population as well as potential side effect of this treatment. These studies will not only establish the role of CD137 signal in Tm growth and functional maturation, but also form the foundation for future development of new approaches in biodefense against pathogens.