PERSISTENCE OF LCMV BY EXHAUSTION OF CYTOTOXIC T CELLS

描述：病毒可以使用许多策略，包括从 免疫识别或诱导免疫抑制，以避免免疫 监视，从而在宿主体内持续存在。通过以下方式阐明这些机制 哪些病毒可以逃避免疫识别对我们理解 病毒致病机制和开发新的治疗策略 病毒感染的治疗，如乙肝和艾滋病毒。病毒式传播 小鼠淋巴细胞性脉络膜脑膜炎病毒感染后的持久性 (LCMV)可通过特异性耐受(“克隆性衰竭”)实现 成熟免疫宿主体内的抗病毒细胞毒性T淋巴细胞(CTL) 系统。我们已经证明，小鼠感染LCMV侵袭性毒株 迅速诱导大量的抗原性负载并驱动激活和 抗原特异性CD8+CTL的大力扩增。在短暂的阶段之后 无反应(不可逆无能)，CD8+CTL永久缺失 发生。由于CD8+CTL对于病毒清除是必不可少的，因此它们的缺失 在体内会导致病毒感染的持久性。“克隆”的耐受性 “耗尽”不会影响病毒特异性的CD4+T细胞，因为抗体 在这些小鼠中依赖于辅助性T细胞的产生未受影响 (拆分公差)。在这项提案中，我们希望延长我们之前的 通过特别关注细胞和分子机制的发现 强调成熟CTL的“克隆性衰竭”。具体目标是 如下：(1)确定淋巴组织的破坏是否 活化的CTL所处的微环境在细胞的腐烂中起作用 抗病毒CTL反应。研究将在小鼠体内缺乏 穿孔素或在Fas/Fas配体依赖的通路中 有助于病毒感染的目标细胞的细胞溶解。(2)审查 抗病毒CTL在小鼠淋巴组织和非淋巴组织中的去向 患有持续的巨细胞病毒感染。细胞凋亡的作用(程序化 细胞死亡)和/或无能(对抗原刺激无反应 体外“克隆衰竭”的抗病毒CTL将被研究 通过对应答的抗病毒CTL进行定量和功能分析。这 将通过使用LCMV特异性的采用转移系统来实现 以转基因CD8+CTL为指标。(3)研究CTL逃逸的作用 通过“克隆”建立持续病毒感染的变异体 抗病毒CTL的耗尽。建议的研究将使用感染的小鼠 具有对一种或多种显性缺乏CTL反应的LCMV变异体 表位多肽。

DESCRIPTION: 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 evade immune recognition is important to our understanding of viral pathogenesis and for the development of new therapeutic strategies for the treatment of viral infections such as hepatitis B and HIV. Viral persistence from infection of murine lymphocytic choriomeningitis virus (LCMV) can be achieved by specific tolerance ("clonal exhaustion") of antiviral cytotoxic T lymphocytes (CTLs) in a host with a mature immune system. We have shown that infection of mice with invasive strains of LCMV rapidly induces a large antigenic load and drives the activation and vigorous expansion of antigen specific CD8+ CTLs. After a transient phase of unresponsiveness (irreversible anergy), permanent deletion of CD8+ CTLs occurs. Since CD8+ CTLs are essential for virus elimination, their deletion in vivo results in the persistence of viral infection. Tolerance by "clonal exhaustion" does not affect virus specific CD4+ T cells since antibody production that is dependent on helper T cells in unaffected in these mice (split-tolerance). In this proposal, we wish to extend our previous findings by specifically focusing on the cellular and molecular mechanisms underlining "clonal exhaustion" of mature CTLs. The specific aims are the following: (1) To determine if destruction of the lymphoid tissue microenvironment by activated CTLs plays a role in the decay of the antiviral CTL response. Studies will be performed with mice deficient in perforin or in Fas/Fas-ligand dependent pathways which principally contribute to cytolysis of virally infected target cells. (2) To examine the fate of antiviral CTLs in lymphoid versus non-lymphoid tissues of mice with a persistent LCMV infection. The contribution of apoptosis (programmed cell death) and/or anergy (unresponsiveness to antigenic stimulation in vitro in the "clona exhaustion" of antiviral CTLs will be studied by quantitation and by functional analyses of responsive antiviral CTLs. This will be accomplished by using an adoptive transfer system with LCMV specific transgenic CD8+ CTLs as indicators. (3) To examine the role of CTL escape variants in the establishment of a persistent viral infection by "clonal exhaustion" of antiviral CTLs. The studies proposed will use mice infected with LCMV variants which lack CTL responses to one or to several dominant epitope peptides.