Elucidation of Human Natural Killer Cell Development

项目摘要 这项建议的重点是阐明过程调节人类自然杀伤（NK）细胞的发展 在健康状态下和在子宫内膜癌（EC）的情况下。NK细胞是细胞毒性的“第1组” 先天性淋巴样细胞（ILC）在免疫中起着无数的作用，对控制恶性肿瘤至关重要。 转型NK细胞在整个免疫系统的各种组织中经历终末分化和成熟。 机体，导致广泛的NK细胞表型和功能。传统NK细胞（cNK） 产生于次级淋巴组织并在血液中占主导地位， 补充T细胞介导的免疫监视。相反，特化的组织驻留NK细胞（trNK） 它们的近亲ILC 1在各种组织中发育，并保留在那里执行不同的功能。 在子宫中，trNK细胞和ILC 1在生理上被设计为通过以下方式支持和促进妊娠： 促进胎盘组织侵入、免疫抑制和血管生成。我们假设在 EC的设置，子宫trNK细胞和ILC 1发育和功能的正常过程被 促进肿瘤细胞的生长和侵袭。我们在本提案中的目标是获得全面的 了解调节健康人NK细胞发育的细胞和分子组分 组织，并确定这些过程是如何影响的设置EC。我们的两个具体目标是：1） 确定NK细胞和ILC 1在人体组织中的发育途径;和2）确定NK细胞如何在人体组织中发育， 发育和功能是由人类EC塑造的。具体而言，在目标1中，我们将检验以下假设： NK细胞和ILC 1来源于一种共同的第1组ILC前体细胞，我们最近在 人类淋巴组织我们提出了一系列的实验来验证我们的假设，并确定 NK细胞相对于ILC 1发育轴的分子调节源自新的前体细胞。 此外，我们将阐明NK细胞和ILC 1在健康人类子宫中的发育途径， 测试子宫NK细胞和ILC 1也来源于类似的第1组ILC前体细胞， 最终通过与淋巴组织不同的途径进行终末分化。在目标2中， 测试NK细胞从常见的第1组ILC前体发育向 产生ILC 1和细胞毒性差的子宫trNK细胞，即使不促进肿瘤，也是允许的 增长通过我们提出的研究，我们将确定NK细胞的发育，功能多样性， 塑性是由EC形成的。这些研究的临床重要性在于EC是最常见的 是美国常见的妇科恶性肿瘤，是美国癌症死亡的第六大原因。 妇女此外，我们预测，从我们的研究中获得的知识将提高我们的基本 了解人类NK细胞发育生物学，并最终设计未来基于免疫的癌症 治疗EC和潜在的其他形式的癌症，其中先天免疫受到影响。

PROJECT SUMMARY This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development in the healthy state and in the setting of uterine endometrial carcinoma (EC). NK cells are cytotoxic “group 1” innate lymphoid cells (ILCs) that play myriad roles in immunity and are vital to controlling malignant transformation. NK cells undergo terminal differentiation and maturation in various tissues throughout the body, leading to a broad spectrum of NK cell phenotypes and functions. So-called conventional NK cells (cNK) that arise in secondary lymphoid tissues and predominate in the blood have established roles in complementing T cell-mediated immune surveillance. In contrast, specialized tissue-resident NK cells (trNK) and their close cousins, ILC1s, develop in various tissues and are retained there to carry out distinct functions. In the uterus, trNK cells and ILC1s are physiologically designed to support and promote pregnancy by promoting placental tissue invasion, immune suppression, and angiogenesis. We hypothesize that in the setting of EC the normal processes of uterine trNK cell and ILC1 development and function are co-opted by the tumor cells to promote their growth and invasion. Our goals in this proposal are to gain a comprehensive understanding of the cellular and molecular components that regulate human NK cell development in healthy tissues and to determine how these processes are impacted in the setting of EC. Our two specific aims are: 1) To define NK cell and ILC1 developmental pathways in human tissues; and 2) To determine how NK cell development and function are shaped by human EC. In particular, in Aim 1 we will test the hypothesis that all NK cells and ILC1s stem from a common group 1 ILC precursor cell, which we have recently identified in human lymphoid tissues. We propose a series of experiments to test our hypothesis and to determine the molecular regulation of the NK cell versus ILC1 developmental axis stemming from the novel precursor cell. Further, we will elucidate the developmental pathways of NK cells and ILC1s in the healthy human uterus, testing the hypothesis that uterine NK cells and ILC1s also stem from a similar group 1 ILC precursor cell but ultimately terminally differentiate through pathways distinct from those in lymphoid tissues. In Aim 2 we will test the hypothesis that NK cell development from the common group 1 ILC precursor is skewed towards the production of ILC1s and poorly cytotoxic uterine trNK cells that are permissive if not promoting of tumor growth. Through our proposed studies we will determine how NK cell development, functional diversity, and plasticity are shaped by EC. The clinical importance of these studies lies in the fact that EC is the most common gynecologic malignancy in the United States and is the sixth leading cause of cancer death in women. Further, we predict that the knowledge gained from our studies will improve our fundamental understand of human NK cell developmental biology and ultimately the design of future immune-based cancer therapies for EC and potentially other forms of cancer in which innate immunity is impacted.