Role of Chemokines on C8+ Tau cell Effector Functions during MCMV infection

描述（由申请人提供）：宿主对微生物病原体的反应包括先天免疫系统和适应性免疫系统的综合作用。对病毒的保护性免疫依赖于细胞因子和趋化因子之间复杂的相互作用来调节先天和适应性效应功能。研究表明，病原体诱导的细胞因子可能决定被感染组织区室中通过诱导特定趋化因子而被激活的细胞成分。T淋巴细胞的激活，特别是CD8+ T细胞，是限制病毒相关的组织损伤和促进mcmv感染组织的病毒清除所必需的。CD8+T细胞对MCMV激活的保护功能已被充分证明，它包括IFN-？和TNF - ?晚期急性感染时。然而，当CD8 T淋巴细胞被招募到感染部位时，它们所起的作用尚未得到评估。研究表明，MCMV诱导肝脏中趋化因子CXCL9和CXCL10的产生，这是两种已知的CXCR3配体。这些都是促进CD8+ T细胞募集到肝脏MCMV位点的关键因素。CXCR3表达于CD8+ T细胞和MCMV特异性CD8+ T细胞亚群的表面，这些细胞在感染期间积聚在肝脏中。本研究旨在确定CXCL9和/或CXCL10在MCMV感染期间促进CD8+ T细胞效应功能中的意义，并探讨这些趋化因子调节CD8 T淋巴细胞效应功能的机制。我们将利用增殖和细胞毒性试验来评估CD8+ T细胞的作用。elisa和流式细胞术分析将用于测定体外细胞因子和趋化因子的产生。我们已经有准备使用的Mig-/-， IP10 -/-和CXCR3 -/-幼崽。获得的结果将有助于理解对病毒感染防御重要的事件，并将有助于确定感染期间保护的关键级联。这也将有助于阐明趋化因子/趋化因子受体在组织部位响应病毒感染的淋巴细胞募集中的功能。

DESCRIPTION (provided by applicant): The host response against microbial pathogens consists of the integrated actions of both the innate and adaptive immune systems. Protective immunity to viruses is dependent upon the complex interactions between cytokines and chemokines to regulate both innate and adaptive effector functions. It has been shown that the cytokines induced by pathogens may determine the cellular components that get activated by inducing specific chemokines in infected tissue compartments. T lymphocyte activation, particularly CD8+ T cells, are required to limit virus-associated tissue damage and the promotion of viral clearance from MCMV-infected tissues. The protective function of CD8+T cells against MCMV activation is well documented and consists of the production of IFN-? and TNF-? during late acute infection. However the role CD8 T lymphocytes play when they are recruited to sites of infection has not been assessed. It has been shown that MCMV induces the production of the chemokines CXCL9 and CXCL10, two known CXCR3 ligands, in the liver. These are key factors in promoting the recruitment of CD8+ T cells to sites of MCMV in the liver. CXCR3 is expressed on the surface of CD8+ T cells and a subset of MCMV- specific CD8+ T cells accumulating in the liver during infection. This proposal seeks to determine the significance of CXCL9 and/or CXCL10, in promoting the effector functions of CD8+ T cells during MCMV infection and to investigate the mechanism by which these chemokines modulate the effector functions of CD8 T lymphocytes. We will make use of proliferation and cytoxicity assays to evaluate the effects of CD8+ T cells. ELISAs and flow cytometry analysis will be used to measure ex vivo cytokine and chemokine production. We already have Mig-/-, IP10 -/- and CXCR3 -/- pups that are ready to be used. The results obtained will contribute to the understanding of events that are important for defense of viral infection and will help to define a critical cascade for protection during infection. It will also help to elucidate the chemokine/ chemokine receptor functions in the recruitment of lymphocytes responding to a virus infection in tissue sites.