ß-1,3-glucan Shaping Natural Killer Cell Immunity

自然杀伤细胞（NK）是细胞免疫细胞系统的第一道防线之一。与适应性免疫细胞如T细胞和B细胞不同，NK历来被认为是先天免疫细胞，它直接杀死病原体，包括细菌、寄生虫和真菌，以及肿瘤细胞和病毒感染的细胞，而不需要事先刺激。这种特性是自然免疫的一部分，因此被称为自然杀伤细胞。然而，最近的研究提供了证据，表明NK细胞对先前遇到的病原体获得增强的反应，这一特性以前归因于适应性免疫细胞，如T细胞和B细胞。NK细胞表现出适应性免疫特性，其中先前的刺激引起刺激（抗原）特异性应答细胞的扩张和持续，从而导致长期免疫和增强效力。几项研究表明抗原特异性NK细胞对小鼠巨细胞病毒（MCMV）、单纯疱疹病毒（HSV）、人巨细胞病毒（HCMV）、丙型肝炎病毒（HCV）、乙型肝炎病毒（HBV）、基孔肯雅病毒或HIV具有记忆样特性。这些研究大多使用完整的微生物。目前尚不清楚真菌，更具体地说，是否有任何有机体的可溶性成分诱导NK细胞适应性免疫记忆。******我们之前的研究表明NK细胞识别并直接杀死真菌，这需要NK细胞接触真菌细胞并形成偶联物。最近，我们证明了天然细胞毒性受体NKp30是NK细胞受体，用于识别和介导对真菌的细胞毒性。最近，我们发现一种多糖β-1,3-葡聚糖是NKp30的结合伙伴，它是真菌细胞壁的组成部分，也是许多细菌和谷物的组成部分。在修订)。此外，我们证明可溶性β-1,3-葡聚糖增强了NK细胞对新型隐球菌和白色念珠菌的细胞毒性，这两种真菌是环境和许多疾病中常见的真菌。β-1,3-葡聚糖增强了NKp30的表达和杀死微生物所需的细胞溶解分子的释放，如穿孔素。然而，目前尚不清楚β-1,3-葡聚糖如何调节NK细胞免疫，以及这种增强的杀伤是否是一种适应性免疫反应。******在本提案中，我们将探索“β-1,3-葡聚糖可以通过结合NKp30的特定结构域来触发NK细胞记忆”的假设。我们将首先剖析NKp30与β-1,3-葡聚糖的相互作用，并确定NKp30和β-1,3-葡聚糖的结合位点。我们将探讨β-1,3-葡聚糖及其结合域在形成NK细胞免疫记忆中的机制和作用。来自这些研究的数据将使我们更好地理解自然界中普遍存在的碳水化合物是否以及如何增强我们的免疫宿主防御系统。

Natural Killer (NK) cells are one of the first lines of defense among the cellular immune cell system. Unlike adaptive immune cells such as T cells and B cells, NK are historically considered innate immune cells that directly kill pathogens, including bacteria, parasites and fungi, as well as tumor cells and virus-infected cells without prior stimulation. This property is part of natural immunity, and hence the name, natural killer cells. However, recent studies have provided evidence that NK cells acquire enhanced responses to previously encountered pathogen, a property previously ascribed to adaptive immune cells such as T and B cells. NK cells show adaptive immune properties in which prior stimulus causes expansion and persistence of a stimulus (antigen)-specific responsive cell that leads to long term immunity with enhanced efficacy. Several studies demonstrated antigen-specific NK cell memory-like properties in response to the mouse cytomegalovirus (MCMV), herpes simplex virus (HSV), human cytomegalovirus (HCMV), Hepatitis C virus (HCV), hepatitis B virus (HBV), chikungunya virus, or HIV. Most of these studies used whole microorganisms. It is unknown whether fungi, and more specifically, whether any soluble components of the organism induce NK cell adaptive immune memory.******Our previous studies showed that NK cells recognize and directly kill fungi, which requires NK cells to contact the fungal cell and form a conjugate. Recently, we demonstrated that the natural cytotoxicity receptor, NKp30, is the NK cell receptor used to recognize and mediate cytotoxicity against fungi. More recently, we discovered that a polysaccharide, β-1,3-glucan, a component of the fungal cell wall, but also a component of many bacteria and cereals, is the binding partner for NKp30 (Nat. Commun. under revision). In addition, we demonstrated that soluble β-1,3-glucan enhanced subsequent NK cell cytotoxicity against Cryptococcus neoformans and Candida albicans, which are common fungi found in the environment and many diseases. β-1,3-glucan enhanced NKp30 expression and release of cytolytic molecules required for killing of microbes, such as perforin. However, it not known how β-1,3-glucan modulates NK cell immunity and whether this enhanced killing is an adaptive immune response.******In this proposal, we will explore the hypothesis that “β-1,3-glucan can trigger NK cell memory by binding to specific domains of NKp30”. We will first dissect interactions of NKp30 with β-1,3-glucan, and determine the binding sites from both NKp30 and β-1,3-glucan. We will investigate the mechanism and effects of β-1,3-glucan or its binding domain in shaping NK cell immunologic memory. Data derived from these studies will better our understanding whether, and how, a ubiquitous carbohydrate in nature strengthens our immune host defense system.