Elucidation of Human Natural Killer Cell Development

这项建议侧重于阐明调节人类自然杀伤(NK)细胞发育的过程。 我们的具体目标是：1)定义微环境(S)，并表征NK细胞的调节 人类次级淋巴组织(SLT)的分化；以及2)定义顺序、调节和 主要组织相容性复合体分子结合受体(MBR)的获得对表型的影响 人NK细胞的成熟。 NK细胞是天然的淋巴样细胞，对肿瘤细胞具有直接的细胞毒作用。NK细胞发挥着重要作用 通过补充T细胞免疫，在免疫监测中发挥重要作用，防止恶性转化 能在异基因造血干细胞移植中发挥重要的移植物抗白血病作用 移植治疗急性髓系白血病(AML)。我们在这项建议中的总体目标是获得全面的 了解调节人类NK细胞发育的细胞和分子成分 功能，以便更好地了解它们是如何工作的，并在面对癌症时能够得到加强。 特别是，在目标1中，我们将定义SLT中人NK细胞所处的细胞微环境(S 发育中间产物(NKDI)驻留和分化。我们之前已经确定并描述了 NKDI在这些组织中的全谱。在过去五年中，更多和密切相关的ILC子集 已经被发现和表征，我们有初步数据表明，所有ILC都源于 自然局限于SLT的常见ILC祖细胞群体。我们假设蜂窝环境 内SLT影响共同的ILC祖细胞的NK细胞分化，我们提出了一系列 验证我们的假说并阐明SLT来源的辅助细胞的机制的实验(S) 种群会影响这一途径。这些研究的目标是确定新的治疗靶点，以促进 急性髓系白血病移植后环境中的免疫功能。 在目标2中，我们有初步数据表明，NK细胞的功能成熟是逐步发生的。 与有序和协调地获得激活受体NKp80和两个 MBR类型：CD94/NKG2A和杀伤免疫球蛋白样受体(KIR)。什么是未知的，也将是 在我们提议的实验中将测试的是这种有序的受体获取是如何被调控的，进而又是如何 通过受体本身的信号影响NK细胞的功能成熟。血管紧张素转换酶的临床重要性 这些研究在于，这些表面NK细胞受体中的每一个都有潜在的靶向 免疫检查点调节，以加强NK细胞介导的抗癌免疫治疗。

This proposal focuses on elucidation of the processes regulating human natural killer (NK) cell development. Our specific aims are: 1) To define the microenvironment(s) and characterize the regulation of NK cell differentiation in human secondary lymphoid tissues (SLT); and 2) To define the order, regulation, and phenotypic impact of major histocompatibility complex molecule binding receptor (MBR) acquisition during human NK cell maturation. NK cells are innate lymphoid cells (ILC) that have direct cytotoxic function against cancer cells. NK cells play a vital role in immune surveillance against malignant transformation by complementing T cell immunity, and they can mediate an important graft-versus-leukemia effect in the setting of allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia (AML). Our overall goal in this proposal is to gain a comprehensive understanding of the cellular and molecular components that regulate human NK cell development and function in order to best understand how they work and can be enhanced in the face of malignancy. In particular, in Aim 1 we will define the cellular microenvironment(s) within SLT in which human NK cell developmental intermediates (NKDI) reside and differentiate. We previously identified and characterized the full spectrum of NKDI in these tissues. Over the past five years, additional and closely-related ILC subsets have been discovered and characterized, and we have preliminary data to indicate that all ILCs derive from a common ILC progenitor population that is naturally restricted to SLT. We hypothesize that the cellular milieu within SLT influences NK cell differentiation from the common ILC progenitor, and we propose a series of experiments to test our hypothesis and also to elucidate the mechanism(s) by which SLT-derived “helper” cell populations influence this pathway. The goal of these studies is to identify new therapeutic targets to boost immune function in the post-transplant setting for AML. In Aim 2 we have preliminary data that suggest that NK cell functional maturation occurs in a stepwise fashion associated with the orderly and coordinated acquisition of the activation receptor, NKp80, and two types of MBRs: CD94/NKG2A and killer immunoglobulin-like receptors (KIR). What is not yet known and will be tested in our proposed experiments is how this orderly acquisition of receptors is regulated and in turn how signaling through the receptors themselves influences NK cell functional maturation. The clinical importance of these studies lies in the fact that each of these surface NK cell receptors has the potential to be targeted for immune checkpoint regulation in order to enhance NK cell-mediated immune therapy against cancer.