Natural killer cell-derived IL-10 and immunity to Listeria

自然杀伤细胞衍生的 IL-10 和对李斯特菌的免疫力

• 批准号: 8975083
• 负责人: Sarah E Clark
• 金额: $ 5.42万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975083
• 关键词: Affect; Bacteria; Bacterial Infections; CD8B1 gene; Cells; Coculture Techniques; Cytolysis; Data; Dendritic Cells; Development; Disease; Encephalitis; Feedback; Gastroenteritis; Goals; Health; Host resistance; Immune; Immune System Diseases; Immune response; Immunity; Immunosuppression; In Vitro; Incidence; Infection; Interferon Type II; Interleukin-10; Interleukin-18; Knowledge; Listeria; Listeria monocytogenes; Listeriosis; Measures; Mediating; Microbe; Modeling; Mus; Myeloid Cells; NK Cell Activation; Natural Killer Cells; Parasitic infection; Phagocytes; Population; Predisposition; Production; Proteins; Regulation; Role; Sepsis; System; T-Lymphocyte; Transcript; Translations; Virus Diseases; Work; adaptive immunity; base; cell type; cytotoxicity; design; foodborne; foodborne pathogen; improved; in vivo; microorganism; neoplastic cell; pathogen; research study; response; therapy design; therapy development; uptake

DESCRIPTION (provided by applicant): The bacterium Listeria monocytogenes (Lm) is one of the most deadly foodborne pathogens, and is particularly dangerous in the immune compromised. How Listeria causes disease and why there is increased susceptibility in some populations remains poorly understood. During infection, Listeria and other microbes can initiate host responses that suppress, rather than contribute to, protective immunity. Identifying how microbes inhibit host immunity is integral to our understanding of host-pathogen interactions and the design of therapies to treat infection. Preliminary data suggest that Lm induces a natural killer (NK) cell-dependent, systemic IL-10 response that limits bacterial clearance. The goals of this proposal are to investigate the induction of NK cell IL-10 production and determine how NK cell-dependent IL-10 limits protective immunity to Lm. First, the stimulation of NK cell-dependent IL-10 in the context of Lm infection will be explored. The effect of IL-18, which contributes to early NK cell IFN-γ production, on NK cell-dependent IL-10 expression will be determined using a co-culture system (with purified NK cells and IL-10-/- dendritic cells) in conjunction with in vio infections in mice that are unresponsive to IL-18. It is also possible that early NK cell IFN-γ affects subsequent IL-10 production. The potential for feedback regulation between NK cell-dependent IFN-γ and IL-10 will be investigated by transferring NK cells from mice that are unresponsive to either IFN-γ or IL-10 into Lm-infected hosts. In the second half of the proposed work, the impact of NK cell-dependent IL-10 on protective immunity will be investigated. Mice with immune cell subsets that are unresponsive to IL-10 will be infected with Lm to determine the cell types required for IL-10-mediated susceptibility. Finally, the impact of NK cell-dependent IL-10 on immune cell protective activity will be evaluated in vivo by measuring CD8+ T cell cytotoxicity during Lm infection in wild-type versus IL-10-/- mice. Collectively, these experiments will explore the requirements for Lm-induced NK cell IL-10 production and establish how this response impacts host protective immunity. This work will expand our knowledge about how microbes can suppress host immunity during infection, which has broad implications for a number of diseases in which the immune response is inappropriately activated.

描述（由适用提供）：单核细胞增生李斯特菌（LM）是最致命的食源性病原体之一，在免疫原子症中尤其危险。李斯特菌如何引起疾病以及为什么某些人群的敏感性增加仍然知之甚少。在感染期间，李斯特菌和其他微生物可以发起抑制受保护免疫学的宿主反应。确定微生物如何抑制宿主免疫学是我们对宿主 - 病原体相互作用的理解以及治疗感染的疗法的设计不可或缺的一部分。初步数据表明，LM诱导了限制细菌清除率的自然杀手（NK）细胞依赖性的全身IL-10反应。该提案的目标是研究NK细胞IL-10产生的诱导，并确定NK细胞依赖性IL-10如何将受保护的免疫学限制为LM。首先，将探索在LM感染的情况下刺激NK细胞依赖性IL-10。 IL-18的影响有助于早期的NK细胞IFN-γ产生，将使用共培养系统（具有纯化的NK细胞和IL-10 - / - 树突状细胞）确定NK细胞依赖性IL-10表达的影响，并在与IL-18的无效小鼠中的VIO感染中结合。生产。通过从对IFN-γ或IL-10无反应的小鼠中转移NK细胞，将研究NK细胞依赖性IFN-γ和IL-10之间反馈调节的潜力。在拟议的工作的下半年，将研究NK细胞依赖性IL-10对受保护免疫学的影响。具有对IL-10无反应的免疫细胞亚群的小鼠将被LM感染，以确定IL-10介导的易感性所需的细胞类型。最后，依赖NK细胞的影响 IL-10在免疫细胞保护活性上，将通过在野生型与IL-10 - / - 小鼠中测量LM感染期间的CD8+ T细胞细胞毒性来评估体内。这些实验总的来说 将探讨对LM诱导的NK细胞IL-10产生的要求，并确定该反应如何影响宿主保护免疫组织化学。这项工作将扩大我们有关微生物如何抑制感染过程中宿主免疫组织化学的知识，这对许多疾病具有广泛的影响，其中免疫治疗反应不当受到适当的激活。