Memory T lymphocyte-mediated innate immunity

描述(由申请人提供)：存储器T细胞(TM)以少量存在于宿主中。一旦再次遇到病原体，TM可以迅速做出反应，增加数量并分化为效应细胞，作为产生强大适应性免疫的一种方式。在这个方案中，我们将研究一种新的现象，即通过连接CD137分子来刺激少量的TM细胞选择性地大量扩增，而不需要再次暴露于抗原。更重要的是，CD137刺激TM细胞的增殖伴随着对病原体的天然免疫功能的获得。在这项提案中，我们将扩大我们的观察范围，以解决对TM介导的天然免疫在未来生物防御中的应用至关重要的基本问题。一个有待检验的中心假设是，CD137刺激激活TM可以诱导对病原体感染的强大天然免疫，并有可能被开发为一种生物防御手段。我们将首先以单核细胞增生性李斯特菌为模型病原体，阐述TM介导的天然免疫的基本特征，包括CD137选择性激活TM的分子基础、天然免疫的动力学以及天然免疫向获得性免疫的转变。我们还将在体内测试CD137刺激直接激活TM亚群产生干扰素-伽马和其他可溶性分子和细胞表面分子，从而激活巨噬细胞和其他效应细胞以消除LM感染的假说。此外，我们还将描述TM介导的天然免疫的细胞和分子成分，以及对TM中CD137信号转导事件的理解。最后，我们将扩展我们的发现，以确定这种方法的治疗潜力，测试CD137刺激在消除LM、老年动物感染、免疫受损人群以及这种治疗的潜在副作用方面的作用。这些研究不仅将确定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新的抗病原体生物防御途径奠定基础。

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.