PERSISTENCE OF LCMV BY EXHAUSTION OF CYTOTOXIC T CELLS

描述：病毒可以使用多种策略，包括逃离 免疫识别或诱导免疫抑制，以避免免疫 监视，从而在宿主中持续存在。 阐明机制， 哪些病毒能逃避免疫识别对于我们理解 病毒的发病机制和发展新的治疗策略， 治疗病毒感染，如B型肝炎和HIV。 病毒 小鼠淋巴细胞性脉络丛脑膜炎病毒感染后的持续性 （LCMV）的特异性耐受性（“克隆耗竭”）可以实现。 具有成熟免疫的宿主中的抗病毒细胞毒性T淋巴细胞（CTL） 系统 我们已经证明，感染LCMV侵袭性毒株的小鼠 快速诱导大的抗原负荷并驱动活化， 抗原特异性CD 8 + CTL的剧烈扩增。 经过一个短暂的阶段 无反应性（不可逆的无反应性），永久性缺失CD 8 + CTL 发生。 由于CD 8 + CTL对于病毒消除是必需的，因此它们的缺失是必要的。 在体内导致病毒感染的持续性。 按“克隆”列出的耐受性 “衰竭”不影响病毒特异性CD 4 + T细胞， 依赖于辅助性T细胞的产生在这些小鼠中不受影响 （分裂容忍度）。 在这一建议中，我们希望扩大我们以前的 通过特别关注细胞和分子机制， 强调成熟CTL的“克隆耗竭”。 具体目标是 以下内容：（1）确定淋巴组织的破坏是否 激活的CTL的微环境在细胞的衰变中起作用。 抗病毒CTL应答。 研究将使用缺乏以下缺陷的小鼠进行： 穿孔素或Fas/Fas配体依赖性途径， 有助于病毒感染的靶细胞的细胞溶解。 (2)审查 抗病毒CTL在小鼠淋巴组织和非淋巴组织中的命运 LCMV持续感染 细胞凋亡（程序性）的贡献 细胞死亡）和/或无反应性（对抗原刺激无反应， 体外抗病毒CTL的“克隆耗竭”将通过 定量和功能分析。 这 将通过使用具有LCMV特异性的过继转移系统来实现 转基因CD 8 + CTL作为指标。 (3)检查CTL转义的作用 在建立持续性病毒感染的变异的“克隆 抗病毒CTL的“耗竭”。 这项研究将使用被感染的小鼠 LCMV变异体缺乏对一种或几种显性CTL应答， 表位肽。

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.