NK cells in CNS inflammation and autoimmunity

描述(申请人提供)：中枢神经系统炎症和自身免疫中的NK细胞项目摘要：自然杀伤(NK)细胞是一种大的颗粒状淋巴细胞，通过细胞溶解活动和细胞因子分泌来运作，是天然免疫系统的重要组成部分。长期以来，我们的研究小组一直有兴趣了解NK细胞在自身免疫性疾病中的生物学功能，特别是它们在中枢神经系统(CNS)炎症和自身免疫中的作用，如多发性硬化症(MS)及其动物模型实验性自身免疫性脑脊髓炎(EAE)。初步数据和相关文献表明，MS/EAE的发生可能源于天然免疫系统细胞和获得性免疫系统细胞(包括NK细胞)之间的相互作用。为了测试这种可能性，我们开发了几种细胞和遗传学方法来系统地和在中枢神经系统中操纵NK细胞，并研究了这些细胞影响中枢神经系统炎症和对髓鞘抗原的自身免疫的能力。我们证明，使用抗NK1.1单抗在所有器官系统中系统性地耗尽NK细胞，或者通过胚系缺失趋化因子受体CX3CR1选择性地减少NK细胞归巢到CNS，导致显著的单核淋巴细胞向CNS渗透，脱髓鞘，以及CNS髓鞘反应性Th17的优先扩张。相反，NK细胞通过与NK细胞上的IL-2受体结合而扩张，显著减弱了中枢神经系统的反应，但不能降低外周Th17细胞的反应。进一步的研究发现，NK细胞位于中枢神经系统的小胶质细胞附近，可以杀死小胶质细胞。当NK细胞耗尽或不能定位于中枢神经系统时，小胶质细胞扩张并产生大量Th17极化细胞因子。此外，NK细胞的缺失促进了Th17系特异性转录因子RORC和STAT3的激活，这种激活依赖于小胶质细胞。在这些初步研究的基础上，我们建议剖析NK细胞介导的EAE保护作用的细胞机制。我们的中心假设是，NK细胞控制着炎症CNS中的小胶质细胞，NK细胞/小胶质细胞的相互作用可以抑制髓鞘反应性Th-17细胞，保护CNS自身免疫。为了验证这一假说，我们将：1)剖析CNS中NK细胞和小胶质细胞之间的相互作用，并确定NK细胞对小胶质细胞的杀伤活性的机制；2)确定NK细胞和小胶质细胞相互作用对CNS中髓鞘反应性CD4+Th17细胞的生成、维持和功能的影响；3)测试基于NK的治疗方法，以保护CNS免受炎症和自身免疫的影响。 公共卫生相关性：NK细胞在中枢神经系统炎症和自身免疫中的作用项目叙述：这项研究将阐明自然杀伤细胞抑制中枢神经系统(CNS)炎症和自身免疫的关键机制。将探讨以NK为基础的治疗干预在预防中枢神经系统炎症中的可行性，并评估其结果，为设计新的中枢神经系统炎症和自身免疫治疗方案提供可能。

DESCRIPTION (provided by applicant): NK cells in CNS inflammation and autoimmunity Project Summary: Natural killer (NK) cells are large, granular lymphocytes that operate through cytolytic activity and cytokine secretion, and represent an important component of the innate immune system. Our group has long been interested in understanding the biological functions of NK cells in autoimmune diseases, particularly their role in inflammation and autoimmunity in the central nervous system (CNS) such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Preliminary data and relevant literature suggest that the initiation of MS/EAE may stem from the interplay between cells of the innate and adaptive immune systems, including NK cells. To test this possibility, we developed several cellular and genetic approaches to manipulate NK cells systemically and in the CNS, and investigated the capacity of these cells to impact the magnitude of CNS inflammation and autoimmunity to myelin antigens. We demonstrated that the systemic depletion of NK cells in all organ system using an anti-NK1.1 mAb, or selectively reduced the homing of NK cells to the CNS through a germ-line deletion of the chemokine receptor CX3CR1, leads to pronounced mononuclear lymphocyitic infiltration into the CNS, demyelination, and preferential expansion of CNS myelin- reactive Th17. Conversely, the expansion of NK cells via the engagement of the IL-2 receptor on NK cells significantly attenuated the CNS, but not peripheral Th17 cell responses. Further investigations revealed that NK cells reside in proximity to microglia in the CNS, and that can kill microglia. When NK cells were depleted or were unable to home to the CNS, microglia expanded and produced large amounts of Th17 polarizing cytokines. Also, the absence of NK cells promoted the activation of the Th17 lineage-specific transcription factors Rorc and STAT3 in a manner that was dependent on microglia. Based on these preliminary studies, we propose to dissect the cellular mechanism governing NK cell-mediated protection from EAE. Our central hypothesis is that NK cells control microglia in the inflamed CNS, and that NK cell/microglia interactions can inhibit myelin-reactive Th-17 cells and protect against CNS autoimmunity. To test this hypothesis, we will: 1) Dissect the interactions between NK cells and microglia in the CNS and identify the mechanism responsible for the cytolytic activity of NK cells against microglia; 2) Define the impact of NK cell/microglia interactions on the generation, maintenance and function of myelin-reactive CD4+ Th17 cells in the CNS; 3) Test NK-based therapeutic approaches for the protection from CNS inflammation and autoimmunity. PUBLIC HEALTH RELEVANCE: NK cells in CNS inflammation and autoimmunity Project Narrative: This study will elucidate key mechanisms by which natural killer (NK) cells can inhibit inflammation and autoimmunity in the central nervous system (CNS). The feasibility of NK-based therapeutic intervention in preventing CNS inflammation will be explored and the outcomes evaluated for possible implementation in the design of novel treatments for CNS inflammation and autoimmunity.