Cellular and molecular mechanisms of NK cell suppression

NK细胞抑制的细胞和分子机制

• 批准号: 8233984
• 负责人: Yasmina Laouar
• 金额: $ 34.99万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-02 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233984
• 关键词: Activated Natural Killer Cell; Adoptive Immunotherapy; Adoptive Transfer; Animal Model; Automobile Driving; Blood; Bone Marrow; Cell Count; Cell Survival; Cell Therapy; Cells; Clonal Expansion; Commit; Competence; Cytolysis; Cytoplasmic Granules; Data; Development; Face; Future; Galium; Genetic; Goals; Granzyme; Health; Immune system; Immunotherapeutic agent; Immunotherapy; In Vitro; Infection; Knowledge; Leukocytes; Ligands; Lymph; Membrane; Messenger RNA; Molecular; Murid herpesvirus 1; Mus; Natural Killer Cells; Outcome; Outcome Study; Pathway interactions; Patients; Pattern; Population; Process; Production; Proliferating; Regulation; Research; Research Design; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Staging; System; Testing; Time; Viral; Virus; Virus Diseases; Work; base; cancer cell; clinical application; combat; cytotoxic; cytotoxicity; design; improved; in vivo; in vivo Model; innovation; insight; killings; novel; programs; response; self-renewal

DESCRIPTION (provided by applicant): Natural Killer (NK) cells are the first line of defense against infection. During their lifetime, NK cells undergo dynamic processes: as they develop, NK cells commit, proliferate, differentiate, and then arrest. Once activated, they immediately acquire cytotoxicity and become quite rapacious in killing target cells. NK cells are predisposed to killing because they are programmed for that function during their development. Our long-term goal is to understand the regulatory mechanisms controlling NK cell dynamics as a prerequisite to the development of successful NK-cell based adoptive immunotherapy. Although the collective efforts, accumulated for the last 20 years, resulted in the identification of key positive regulators of NK cells, the current knowledge failed to identify or elucidate the mechanisms of NK cell negative regulation. We searched for potential candidates and successfully identified TGF? as a potent negative regulator of NK cells1. To date, TGF? remains the only identified negative regulator of NK cell number. Therefore, it is imperative that the mechanisms by which TGF? operate in NK cells are understood. The specific hypothesis driving the proposed research is that TGF? limits the production and restricts the cytotoxicity acquisition of NK cells in response to viral infection. This hypothesis is based on three preliminary data: First, lack of TGF?R signaling results in augmented production of NK cells at terminal differentiation in the bone marrow. Second, lack of TGF?R signaling revealed a previously undescribed population of Granzyme Blow NK cells which is otherwise suppressed in normal mice. Third, mice having TGF?-resistant Granzyme Blow NK cells are resistant to murine cytomegalovirus. Using a combination of in vitro and in vivo approaches, we will test our hypothesis in two Specific Aims: In Aim 1, we will determine the mechanisms by which TGF? controls the production of NK cells. Two studies are designed to investigate i)-how TGF? regulates the processes of differentiation, survival, and proliferation during the production of NK from the bone marrow, and i)-why NK cells at their terminal differentiation are particularly susceptible to TGF? signaling. One prerequisite for the development of successful NK-cell-based immunotherapy in the future is to determine the factors that condition the survival, expansion, and self renewal of NK cells. The possibility that a lack of TGF?R signaling can prolong NK cell survival will support the notion that blocking the TGF?R pathway in NK cells prior to adoptive transfer into patients is a possibility for improving the design of NK-cell-based immunotherapeutic strategies. In Aim 2, we will determine the mechanism by which TGF? restricts functional competence of NK cells during response infection. Three studies were designed to determine direct outcomes of a lack of TGF?R signaling on i)- acquisition of cytotoxicity, ii)-clonal expansion and contraction in response to viral infection, and iii)-tolerance to viral ligands. We believe that understanding how negative regulation by TGF? restricts NK cell cytotoxicity will provide a strategy to make NK cells stronger in facing evolving viruses.

描述（由申请人提供）：自然杀伤（NK）细胞是抵御感染的第一道防线。在它们的一生中，NK细胞经历了一个动态的过程：随着它们的发育，NK细胞承诺，增殖，分化，然后停止。一旦被激活，它们立即获得细胞毒性，并变得非常贪婪地杀死目标细胞。NK细胞倾向于杀戮，因为它们在发育过程中就被设定了这种功能。我们的长期目标是了解控制NK细胞动力学的调节机制，这是成功开发基于NK细胞的过继免疫疗法的先决条件。尽管在过去20年的共同努力下，我们发现了NK细胞的关键正调节因子，但目前的知识还未能识别或阐明NK细胞负调节的机制。我们搜索了潜在的候选者，并成功地鉴定出TGF？作为NK细胞的有效负调节因子1。迄今为止，TGF？仍然是唯一确定的NK细胞数量负调节因子。因此，迫切需要研究TGF？在NK细胞中起作用我们提出的研究的具体假设是：TGF？在病毒感染的反应中，限制NK细胞的产生和细胞毒性获得。这一假设基于三个初步数据：第一，TGF？R信号导致骨髓中NK细胞在终末分化时的扩增。二是TGF？R信号显示了先前未描述的Granzyme Blow NK细胞群，否则在正常小鼠中被抑制。第三，TGF？NK细胞对小鼠巨细胞病毒具有耐药性。结合体外和体内方法，我们将在两个特定目标中验证我们的假设：在Aim 1中，我们将确定TGF？控制NK细胞的产生。两项研究旨在探讨1)TGF如何？调节骨髓NK细胞产生过程中的分化、存活和增殖过程，以及i)-为什么NK细胞在分化末期特别容易受到TGF的影响？信号。未来成功发展NK细胞免疫疗法的一个先决条件是确定影响NK细胞生存、扩增和自我更新的因素。TGF缺乏的可能性？R信号可以延长NK细胞的存活，这支持了阻断TGF？在过继转移到患者体内之前，NK细胞中的R通路可能会改善NK细胞免疫治疗策略的设计。在Aim 2中，我们将确定TGF？在应答性感染中限制NK细胞的功能能力。三项研究旨在确定TGF？i)细胞毒性的获得，ii)响应病毒感染的克隆扩增和收缩，以及iii)对病毒配体的耐受性。我们认为了解TGF是如何负调控的？限制NK细胞的细胞毒性将提供一种策略，使NK细胞在面对不断进化的病毒时更强大。