Key Innate Mechanisms of Natural Killer Cell Trafficking

自然杀伤细胞贩运的关键先天机制

• 批准号: 6796827
• 负责人: THAIS P. SALAZAR-MATHER
• 金额: $ 25.34万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6796827
• 关键词: Kupffer' s cell; RNase protection assay; bioassay; cell migration; cell population study; chemokine; cytokine; cytokine receptors; cytomegalovirus; dendritic cells; flow cytometry; genetically modified animals; histology; host organism interaction; immunologic assay /test; interferons; laboratory mouse; leukocytes; liver infection; macrophage; macrophage inflammatory proteins; microarray technology; microorganism immunology; monocyte chemoattractant protein 1; natural killer cells

DESCRIPTION (provided by applicant): NK cells have been shown to be important in defense against tumors and infections. The overall goal of this study is to characterize key molecular events controlled by innate cytokines and chemokines for promoting the recruitment of NK cells for delivery of antiviral defense and downstream T cell responses to liver. A protective role for NK cells and NK cell-derived IFN-gamma during MCMV infection has been clearly established. During MCMV infections of mice the chemokine MIP-1alpha/CCL3 promotes NK cell migration and delivery of IFN-gamma at tissues sites of viral infection to mediate downstream protective responses. Recently, type 1 interferons (IFN-alpha/beta) were identified as key initiators of the MIP-1alpha production that is necessary for NK cell inflammation and innate protection against MCMV. These studies defined a cellular delivery mechanism by which innate cytokines promote local immune responses. Experiments planned here will provide new insights into the intrinsic cytokine-chemokine networks that regulate localized recruitment of innate effector cells for antiviral defense, as well as characterize the cytokine-chemokine functions that shape adaptive immune responses. The focal hypotheses are that (i) IFNalpha/beta-mediated recruitment of MIP-l?-producing cells in liver during MCMV infection occurs as a result of the following steps: 1) infection in liver induces the release of IFN-alpha/beta from uninfected or infected macrophage populations, Kupffer cells, and/or dendritic cell subsets, 2) to induce production of intermediary chemokines, e.g. MCP-1/CCL2, and/or chemokine receptors, e.g. CCR2, 3) to promote NK cell trafficking and innate antiviral defense; and (ii) NK cell inflammatory responses help shape adaptive immunity by: 1) inducing production of IFNgamma-inducible chemokines, 2) that mediate recruitment of T lymphocytes during late MCMV infection in liver. These will be examined by asking the following questions in 3 Specific AIMS. 1) What cell types are induced to produce IFN-alpha/beta during virus infection and what are the contributions of virus to cytokine production in liver? 2) What are the chemokines and chemokine producers, as well as the target cells, activated or responding to IFN-alpha/beta 3) Are gamma-inducible chemokines mediating downstream T cell responses in liver? Molecular, histological, immunological, and cell trafficking studies will be used to answer these questions. The experiments will take advantage of mice genetically deficient in chemokine or chemokine receptors.

描述（由申请人提供）：NK 细胞已被证明在防御肿瘤和感染方面非常重要。本研究的总体目标是表征由先天细胞因子和趋化因子控制的关键分子事件，以促进 NK 细胞的募集，以提供抗病毒防御和下游 T 细胞对肝脏的反应。 NK 细胞和 NK 细胞衍生的 IFN-γ 在 MCMV 感染期间的保护作用已明确确定。在小鼠 MCMV 感染期间，趋化因子 MIP-1α/CCL3 促进 NK 细胞迁移并在病毒感染的组织部位传递 IFN-γ，以介导下游保护反应。最近，1 型干扰素 (IFN-α/β) 被确定为 MIP-1α 产生的关键启动子，MIP-1α 是 NK 细胞炎症和针对 MCMV 的先天保护所必需的。这些研究定义了一种细胞传递机制，先天细胞因子通过该机制促进局部免疫反应。这里计划的实验将为内在细胞因子-趋化因子网络提供新的见解，该网络调节先天效应细胞的局部募集以进行抗病毒防御，并表征形成适应性免疫反应的细胞因子-趋化因子功能。焦点假设是(i) MCMV感染期间肝脏中IFNα/β介导的MIP-1α生成细胞的募集是由于以下步骤而发生的：1)肝脏中的感染诱导IFN-α/β的释放来自未感染或感染的巨噬细胞群、库普弗细胞和/或树突细胞亚群，2)诱导中间趋化因子的产生，例如趋化因子。 MCP-1/CCL2，和/或趋化因子受体，例如CCR2, 3) 促进 NK 细胞运输和先天抗病毒防御； (ii) NK 细胞炎症反应通过以下方式帮助形成适应性免疫：1) 诱导 IFNγ 诱导趋化因子的产生，2) 在肝脏晚期 MCMV 感染期间介导 T 淋巴细胞的募集。这些将通过在 3 个具体目标中提出以下问题来进行检查。 1) 在病毒感染过程中，哪些细胞类型被诱导产生 IFN-α/β？病毒对肝脏细胞因子产生的贡献是什么？ 2) 激活或响应 IFN-α/β 的趋化因子和趋化因子产生者以及靶细胞是什么 3) γ 诱导型趋化因子是否介导肝脏中的下游 T 细胞反应？分子、组织学、免疫学和细胞运输研究将用于回答这些问题。这些实验将利用遗传上缺乏趋化因子或趋化因子受体的小鼠。