Memory T lymphocyte-mediated innate immunity

描述（由申请人提供）：记忆T细胞（Tm）在宿主体内少量存在。当再次遇到病原体时，Tm可以迅速反应以增加数量并分化为效应细胞，从而产生有效的适应性免疫。在本研究中，我们将研究一种新的现象，即通过连接CD137分子的刺激，少量的Tm细胞可以选择性地扩增成大量，而无需再次暴露于抗原。更重要的是，CD137刺激下的Tm细胞增殖伴随着对病原体的先天免疫功能的获得。在本提案中，我们将扩展我们的观察，以解决对tm介导的先天免疫在生物防御中的未来应用至关重要的基本问题。一个有待验证的中心假设是，CD137刺激激活Tm可以诱导对病原体感染的强效先天免疫，并可能发展成为生物防御的一种手段。我们将首先讨论Tm介导的先天免疫的基本特征，包括CD137选择性激活Tm的分子基础，先天免疫动力学和先天免疫向适应性免疫的转变，以单核增生李斯特菌（Listeria monocytogenes， LM）为模型病原体。我们还将在体内验证cd137刺激直接激活Tm亚群产生ifn - γ和其他可溶性和细胞表面分子，从而激活巨噬细胞和其他效应细胞以消除LM感染的假设。此外，我们将描述Tm介导的先天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，我们将扩展我们的研究结果，以确定这种方法的治疗潜力，测试CD137刺激在消除LM中的作用，老年动物感染，免疫受损人群以及这种治疗的潜在副作用。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，也将为未来生物防御病原体的新方法的开发奠定基础。

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.