Cellular and molecular mechanisms of NK cell suppression

NK细胞抑制的细胞和分子机制

• 批准号: 8627107
• 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/8627107
• 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）细胞是抵抗感染的第一道防线。在其生命周期中，NK细胞经历动态过程：随着它们的发育，NK细胞定型、增殖、分化，然后停滞。一旦被激活，它们立即获得细胞毒性，并在杀死靶细胞方面变得非常贪婪。NK细胞倾向于杀人，因为它们在发育过程中被编程为这种功能。我们的长期目标是了解控制NK细胞动力学的调节机制，这是开发成功的基于NK细胞的过继免疫疗法的先决条件。尽管在过去20年中积累的集体努力导致了NK细胞的关键正调节因子的鉴定，但目前的知识未能鉴定或阐明NK细胞负调节的机制。我们寻找潜在的候选人，并成功地确定了TGF？作为NK细胞的有效负调节剂1。迄今为止，TGF？仍然是唯一确定的NK细胞数量的负调节因子。因此，这是必要的，TGF？在NK细胞中起作用。具体的假设驱动拟议的研究是，TGF？限制了NK细胞的产生并限制了NK细胞响应病毒感染的细胞毒性获得。这一假设是基于三个初步的数据：第一，缺乏TGF？R信号传导导致骨髓中NK细胞在终末分化时的产生增加。第二，缺乏TGF？R信号揭示了以前未描述的粒酶Blow NK细胞群体，其在正常小鼠中被抑制。第三，具有TGF？抗粒酶Blow NK细胞对鼠巨细胞病毒具有抗性。使用体外和体内方法相结合，我们将测试我们的假设在两个具体目标：在目标1，我们将确定的机制，TGF？控制NK细胞的产生。两项研究的目的是调查i）-如何TGF？在从骨髓产生NK的过程中调节分化、存活和增殖的过程，以及i）-为什么NK细胞在其终末分化时对TGF特别敏感？信号未来成功开发基于NK细胞的免疫疗法的一个先决条件是确定影响NK细胞存活、扩增和自我更新的因素。缺乏TGF的可能性？R信号可以延长NK细胞的生存将支持的概念，阻断TGF？在过继转移到患者体内之前，NK细胞中的R途径是改进基于NK细胞的免疫策略设计的可能性。在目标2，我们将确定的机制，TGF？在应答感染期间限制NK细胞的功能能力。三项研究的目的是确定缺乏TGF？R信号传导对i）细胞毒性的获得，ii）响应于病毒感染的克隆扩增和收缩，和iii）对病毒配体的耐受性。我们认为，了解如何负调节TGF？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。