The role of Notch signaling in human natural killer cell functional maturation

Notch信号在人类自然杀伤细胞功能成熟中的作用

• 批准号: 9921194
• 负责人: Ansel Peter Nalin
• 金额: $ 3.97万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9921194
• 关键词: Acute Myelocytic Leukemia; Address; Adoptive Transfer; Allogenic; Antigens; Aryl Hydrocarbon Receptor; Autologous; Bioinformatics; Cell Maturation; Cell physiology; Cells; Cellular biology; Cellular immunotherapy; Clinical; Coculture Techniques; Complement; Data; Dendritic Cells; Development; Disease; Exposure to; Gene Targeting; Genes; Genetic Transcription; Goals; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Immunology; Impairment; In Vitro; Innate Immune Response; Interferon Type II; Knowledge; Laboratories; Large granular lymphocyte; Lymphoid Tissue; Malignant Neoplasms; Mediating; MicroRNAs; Mus; Natural Killer Cells; Notch Signaling Pathway; Pathway interactions; Patients; Phenotype; Physiological; Play; Process; Publishing; Receptor Activation; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Stress; Surface; T-Lymphocyte; Testing; Tonsil; Transcriptional Regulation; Translational Research; Transplantation; Tumor Immunity; Work; base; cancer cell; cancer immunotherapy; cancer therapy; clinical application; cytotoxicity; experimental study; graft vs leukemia effect; immunoregulation; improved; in vivo; innovation; loss of function; lymph nodes; notch protein; novel; p80 natural killer cell receptor; perforin; peripheral blood; post-transplant; prevent; receptor; response; stem cells; transcription factor; tumor immunology

PROJECT SUMMARY/ABSTRACT Our long-term goal in this project is to elucidate the mechanisms of human natural killer cell development in order to apply the processes of NK cell biology in the treatment of cancer. Natural killer (NK) cells recognize malignant cells lacking self-MHC molecules on their surface, thus targeting them for perforin-mediated cytotoxicity. NK cells comprise an important role in the innate immune response to malignancy, and indeed cancers such as acute myeloid leukemia (AML) have been shown to have impaired NK cell development and function. Therefore, understanding the yet unknown mechanisms regulating NK cell maturation in both the normal and disease settings will improve translational research efforts for cancer therapy. Our ongoing work investigates NK cell developmental pathways occurring in secondary lymphoid tissues (SLTs; including tonsils and lymph nodes). In our current studies, we observed that activation of the Notch signaling pathway results in a key transition during development from a non-functional phenotype to a functionally mature NK cell. Moreover, we detected constitutive expression of the transcriptionally-active domain of Notch in mature NK cells freshly isolated from tonsils, thus supporting the physiologic importance of Notch in regulating the functional phenotype of mature NK cells. We hypothesize that Notch signaling in the SLT microenvironment regulates the developmental transition from immature to functional NK cells. We further hypothesize that signaling through the aryl hydrocarbon receptor (AHR), which we observe is activated in AML, alters Notch signaling to inhibit NK cell development. Thus our aims are 1) to determine the mechanism by which Notch is activated in SLTs to promote NK cell functional maturation; and 2) to determine how AHR modulates Notch to antagonize NK cell maturation. To test this hypothesis, we will perform in vitro culture studies and in vivo adoptive transfer experiments using NK and other SLT-resident cells isolated from human tonsils. We will identify the direct gene targets of activated Notch in NK cells to determine how Notch regulates the transcription of critical molecules for NK cell function. Finally, we will identify how AHR modulates Notch signaling in NK cells. The overall significance of this project will address a relevant gap in knowledge regarding the regulation of human NK cell maturation in the SLT microenvironment. This project represents a novel and innovative approach to cancer immunology because it combines both mechanistic studies of an important signaling pathway, and also seeks to identify how cancers such as AML can evade the human immune system. Successful completion of these aims will improve our understanding of the normal processes of NK cell development with the goal of applying these discoveries toward novel immune-based therapies for cancer.

项目摘要/摘要 我们在该项目中的长期目标是阐明人类自然杀伤细胞开发的机制 为了将NK细胞生物学的过程应用于癌症的治疗。天然杀手（NK）细胞识别 表面上缺乏自MHC分子的恶性细胞，因此将其靶向穿孔蛋白介导 细胞毒性。 NK细胞在对恶性肿瘤的先天免疫反应中构成了重要作用，实际上 诸如急性髓样白血病（AML）之类的癌症已显示出损害NK细胞的发育和 功能。因此，了解调节NK细胞成熟的未知机制 正常和疾病的环境将改善癌症治疗的转化研究工作。我们正在进行的工作 研究发生在次级淋巴组织中的NK细胞发育途径（SLT；包括扁桃体 和淋巴结）。在目前的研究中，我们观察到Notch信号通路的激活导致 从非功能表型到功能成熟的NK细胞的开发过程中的关键过渡。而且， 我们检测到成熟NK细胞中Notch转录活性结构域的本构表达 从扁桃体中分离出来，从而支持Notch在调节功能表型中的生理重要性 成熟的NK细胞。我们假设SLT微环境中的Notch信号传导调节 从不成熟到功能性NK细胞的发育过渡。我们进一步假设通过 我们观察到的芳基烃受体（AHR）在AML中激活，改变了Notch信号抑制NK细胞 发展。因此，我们的目标是1）确定在SLT中激活Notch以促进的机制 NK细胞功能成熟； 2）确定AHR如何调节Notch以拮抗NK细胞的成熟。 为了检验这一假设，我们将使用体外培养研究和使用体内过继的转移实验 NK和其他从人类扁桃体中分离出来的SLT居民细胞。我们将确定激活的直接基因靶标 NK细胞中的Notch确定Notch如何调节NK细胞功能的临界分子的转录。 最后，我们将确定AHR如何调节NK细胞中的Notch信号传导。该项目的总体意义 将解决有关SLT中人类NK细胞成熟调节的知识的相关差距 微环境。该项目代表了一种新颖而创新的癌症免疫学方法，因为它 结合了重要的信号通路的两种机械研究，也试图确定癌症的方式 例如AML可以逃避人类免疫系统。这些目标的成功完成将改善我们的 了解NK细胞开发的正常过程，目的是将这些发现应用于 新颖的基于免疫的癌症疗法。