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

描述(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获得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的复杂相互作用来调节先天和获得性效应器功能。已有研究表明，病原体诱导的细胞因子可能决定了通过在感染组织中诱导特定的趋化因子而激活的细胞成分。T淋巴细胞的激活，特别是CD8T细胞，是限制病毒相关的组织损伤和促进病毒从MCMV感染组织中清除所必需的。CD8T细胞对MCMV激活的保护作用已得到很好的证实，其功能包括产生干扰素？和肿瘤坏死因子-？在晚期急性感染期间。然而，CD8 T淋巴细胞在被招募到感染部位时所起的作用尚未得到评估。已有研究表明，MCMV可诱导肝脏产生趋化因子CXCL9和CXCL10，这是两种已知的CXCR3配体。这些都是促进CD8T细胞向肝脏中MCMV部位募集的关键因素。CXCR3表达在CD8 T细胞表面和感染期间在肝脏中积聚的MCMV特异性CD8 T细胞亚群上。本研究旨在确定CXCL9和/或CXCL10在MCMV感染过程中促进CD8T细胞效应功能的意义，并探讨这些趋化因子调节CD8T细胞效应功能的机制。我们将利用增殖和细胞毒试验来评估CD8T细胞的作用。ELISA和流式细胞术将用于测量体外细胞因子和趋化因子的产生。我们已经有Mig-/-，IP10-/-和CXCR3-/-PUP可以使用了。所获得的结果将有助于理解对防御病毒感染非常重要的事件，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对病毒感染作出反应的淋巴细胞的招募功能。

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.