Enhancement of CD8 T Cell Immunity by IL-7 Therapy

描述（由申请人提供）：人类病毒性出血热（VHP）是由几种病原引起的，包括沙粒病毒、布尼亚病毒和丝状病毒。这些病原体已被NIAID列为A类病原体，因为它们有可能被用于生物恐怖主义和生物战行为中的故意暴露。除了与这些感染相关的高发病率和死亡率外，临床疾病的特点是症状发作和死亡迅速。因此，迫切需要开发有效的疫苗和免疫治疗策略，以对抗这些往往致命的感染。旧大陆沙粒病毒包括拉沙病毒和原型淋巴细胞脉络丛脑膜炎病毒（LCMV）。与LCMV类似，CDS T细胞介导的免疫可能对防御拉沙热很重要，因此，针对这些试剂的疫苗需要引发有效的CDS T细胞记忆。通常，CDS T细胞反应可分为三个不同的阶段：(1)扩增阶段，初始T细胞被激活，进行克隆扩增和分化为效应细胞；(2)收缩期，约95%的效应CDS T细胞发生凋亡；(3)记忆期，其余5%的CDS T细胞作为记忆T细胞维持较长时间。这些记忆CDS T细胞通过迅速扩增和分化为效应细胞，赋予抗再感染的保护性免疫。保护性免疫的发展取决于一定数量的记忆CDS T细胞的产生，因此人们对增加疫苗诱导的记忆T细胞的数量非常感兴趣。使用具有良好特征的LCMV感染小鼠模型，我们已经获得了强有力的初步数据，表明在CDS T细胞反应的收缩阶段，IL-7治疗导致病毒特异性记忆CDS T细胞数量的大幅增加。了解IL-7诱导的CDS T细胞记忆增强的机制是本应用的重点。具体目的是确定：(1)使用最先进的表型和功能分析，IL-7治疗对淋巴和非淋巴器官中CDS T细胞长期记忆的“数量”和“质量”的影响；(2) il -7诱导CDS T细胞记忆增强的细胞和分子基础。具体目标2将通过检查IL-7治疗对lcmv特异性CDS T细胞增殖和凋亡的影响，以及使用转基因和敲除小鼠研究BCL-2、MCL-1和BIM在调节IL-7诱导效应中的作用来解决。拟议的研究应有助于合理设计疫苗，以产生有效的CDS T细胞记忆，并防止痘病毒和沙粒病毒感染。

DESCRIPTION (provided by applicant): Viral hemorrhagic fever (VHP) in humans is caused by several etiologic agents including arenaviruses, bunyaviruses, and filoviruses. These agents have been classified as category A pathogens by the NIAID because of their potential of being used for intentional exposure in acts of bioterrorism and biological warfare. In addition to the high rate of morbidity and mortality associated with these infections, clinical disease is characterized by rapid onset of symptoms and death. Therefore, there is a critical need to develop effective vaccines and immunotherapeutic strategies to combat these often-fatal infections. The Old World arenaviruses include Lassa virus and the prototypic lymphocytic choriomeningitis virus (LCMV). Similar to LCMV, CDS T cell-mediated immunity is likely to be important for defense against Lassa fever and therefore, vaccines against these agents need to elicit potent CDS T cell memory. Typically, CDS T cell responses can be divided into three distinct phases: (1) expansion phase when naive T cells get activated to undergo clonal expansion and differentiation into effector cells; (2) contraction phase when ~95% of the effector CDS T cells undergo apoptosis, and (3) memory phase during which the remaining 5% of the CDS T cells are maintained as memory T cells for extended periods of time. These memory CDS T cells confer protective immunity against re- infection by rapidly expanding and differentiating into effector cells. The development of protective immunity depends upon the generation of a critical number of memory CDS T cells, and there is high level of interest to boost the number of vaccine-induced memory T cells. Using the well-characterized mouse model of LCMV infection, we have obtained strong preliminary data that IL-7 therapy during the contraction phase of the CDS T cell response led to a substantial enhancement in the number of virus-specific memory CDS T cells. Understanding the mechanisms underlying the IL-7- induced enhancement in CDS T cell memory is the focus of this application. The specific aims are to determine the: (1) effects of IL-7 therapy on the 'quantity' and 'quality' of long-term CDS T cell memory in both lymphoid and non-lymphoid organs using the state-of-the-art phenotypic and functional assays; (2) cellular and molecular basis of IL-7-induced enhancement of CDS T cell memory. Specific aim 2 will be addressed by examining the effect of IL-7 therapy on the proliferation and apoptosis of LCMV-specific CDS T cells and investigating the role of BCL-2, MCL-1, and BIM in regulating IL-7-induced effects using transgenic and knockout mice. The proposed studies should aid in the rational design of vaccines that can engender potent CDS T cell memory and protect against poxvirus and arenaviral infections.