Persistence of LCMV by exhaustion of antiviral T cells

描述（由申请人提供）：病毒可以使用多种策略 包括逃避免疫识别或诱导免疫抑制， 避免免疫监视，从而在宿主中持续存在。阐明 病毒持续存在并逃避免疫监视的机制是 这对我们理解病毒的发病机理和发展 采取措施控制和消除这类感染及其引起的疾病。 侵袭性淋巴细胞株感染后的病毒持久性 脉络丛脑膜炎病毒（LCMV）可以通过选择性下调 病毒特异性T细胞介导的宿主应答的克隆耗竭（“克隆耗竭”） 拥有成熟的免疫系统在这种情况下，发病时的高病毒负荷 的感染驱动响应细胞毒性CD 8 + T细胞（CTL）进入不同的细胞， 耗竭的程序，如无反应性的诱导（功能性的 无响应性）和/或删除。这种病毒特异性CD 8 + T细胞的抑制 感染早期的反应导致长期或永久的 持续感染。“克隆衰竭”耐受性也影响病毒 特异性CD 4 + T细胞及其功能失活可以促进永久性免疫应答。 病毒感染的持续性。在这一建议中，我们希望扩大我们的 通过专门关注分子机制， 成熟宿主中病毒特异性T细胞的“克隆耗竭”。具体 目的如下：（1）解剖特定的病毒决定因素， 通过“克隆耗竭”建立持续性病毒感染的作用 病毒特异性T细胞。(2)为了检测抗原呈递的贡献， 细胞与T细胞的相互作用导致病毒特异性T细胞的“克隆耗竭” 细胞与持续LCMV感染的小鼠。(3)检查分子 诱导病毒特异性T细胞的T细胞受体信号传导机制 无反应性和/或缺失。详细的见解 研究病毒与免疫系统的相互作用， 更充分的疫苗和治疗策略，也将帮助我们 更好地了解免疫系统。

DESCRIPTION (provided by applicant): Viruses can use a number of strategies including escape from immune recognition or induction of immunosuppression to avoid immunological surveillance and thereby persist in the host. Elucidating the mechanisms by which viruses persist and escape immune surveillance is important to our understanding of viral pathogenesis and for the development of measures to control and eliminate such infections and the diseases they cause. Viral persistence following infection with invasive strains of lymphocytic choriomeningitis virus (LCMV) can be achieved by selective down-regulation ("clonal exhaustion") of the virus-specific T cell mediated response in a host with a mature immune system. In this scenario, high viral burden at the onset of infection drives responding cytotoxic CD8+ T cells (CTLs) into different programs of exhaustion such as induction of anergy (functional unresponsiveness) and/or deletion. This dampening of virus-specific CD8+ T cell responses in the early phase of infection results in a protracted or permanent persistence of infection. Tolerance by "clonal exhaustion" also affects virus specific CD4+ T cells and their functional inactivation can promote a permanent persistence of the viral infection. In this proposal, we wish to extend our previous findings by specifically focusing on molecular mechanisms underlining "clonal exhaustion" of virus-specific T cells in a mature host. The specific aims are the following: (1) To dissect specific viral determinants playing a role in establishment of a persistent viral infection by "clonal exhaustion" of virus-specific T cells. (2) To examine the contribution of antigen presenting cell interactions with T cells to the "clonal exhaustion" of virus-specific T cells in mice with a persistent LCMV infection. (3) To examine molecular mechanisms in T cell receptor signaling that induce virus-specific T-cell anergy and/or deletion during chronic LCMV infection of mice. Detailed insight into interaction of viruses with the immune system stands to generate concepts for more adequate vaccine and therapeutic strategies and will also help us to better understand the immune system.