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

描述（由申请人提供）：单核细胞增生李斯特菌（Lm）是最致命的食源性病原体之一，对免疫功能低下的人尤其危险。李斯特菌是如何引起疾病的以及为什么在一些人群中易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启动宿主抑制而不是促进保护性免疫的反应。确定微生物如何抑制宿主免疫对于我们理解宿主-病原体相互作用和设计治疗感染的疗法是不可或缺的。初步数据表明，Lm诱导自然杀伤（NK）细胞依赖的全身IL-10反应，限制细菌清除。本提案的目的是研究NK细胞IL-10的诱导产生，并确定NK细胞依赖性IL-10如何限制对Lm的保护性免疫。首先，将探讨NK细胞依赖性IL-10在Lm感染背景下的刺激。IL-18对早期NK细胞IFN-？将使用共培养系统（纯化NK细胞和IL-10-/-树突状细胞）结合对IL-18无反应的小鼠体内感染来确定NK细胞依赖性IL-10表达的生产。也有可能早期NK细胞IFN-？影响后续IL-10的生产。NK细胞依赖性IFN-？和IL-10将通过从对IFN-？或IL-10进入被lm感染的宿主在拟议工作的后半部分，将研究NK细胞依赖性IL-10对保护性免疫的影响。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介导的敏感性所需的细胞类型。最后，NK细胞依赖性的影响

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-? 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-? affects subsequent IL-10 production. The potential for feedback regulation between NK cell-dependent IFN-? and IL-10 will be investigated by transferring NK cells from mice that are unresponsive to either IFN-? 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.