Elucidation of Human Natural Killer Cell Development

该提案的重点是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）确定NK细胞的微环境和表征NK细胞的调节 2）确定人类次级淋巴组织（NHL）的分化顺序，调节， 主要组织相容性复合体分子结合受体（MBR）获得的表型影响 人NK细胞成熟。 NK细胞是先天性淋巴样细胞（ILC），其具有针对癌细胞的直接细胞毒性功能。NK细胞发挥着 通过补充T细胞免疫，在免疫监视中对恶性转化起重要作用， 在异基因造血干细胞的情况下， 急性髓细胞白血病（AML）的移植。我们在本提案中的总体目标是获得一个全面的 了解调节人类NK细胞发育的细胞和分子组分， 功能，以便最好地了解它们是如何工作的，并且可以在恶性肿瘤面前得到增强。 特别地，在目标1中，我们将定义人NK细胞在其中增殖的细胞微环境。 发育中间体（NKDI）的存在和分化。我们以前确定并描述了 这些组织中的NKDI全谱在过去五年中，其他密切相关的国际劳工组织子集 已经被发现和表征，我们有初步的数据表明，所有的ILC来自 一种常见的ILC祖细胞群体，其自然地限于E1。我们假设细胞环境 内分泌干扰物影响NK细胞从共同ILC祖细胞分化，我们提出了一系列的 实验来验证我们的假设，也阐明了SLT衍生的“辅助”细胞 人口影响这条道路。这些研究的目标是确定新的治疗靶点，以促进 AML移植后的免疫功能。 在目标2中，我们有初步数据表明NK细胞功能成熟是逐步发生的， 与活化受体NKp 80的有序和协调获得相关的方式，以及两个 MBR类型：CD 94/NKG 2A和杀伤免疫球蛋白样受体（KIR）。目前还不清楚的是， 在我们提出的实验中要测试的是受体的有序获得是如何调节的， 通过受体本身的信号传导影响NK细胞功能成熟。的临床重要性 这些研究在于这样一个事实，即这些表面NK细胞受体中的每一种都具有靶向 免疫检查点调节以增强NK细胞介导的针对癌症的免疫疗法。

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.