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

自然杀伤细胞是细胞免疫系统的第一道防线。与T细胞和B细胞等适应性免疫细胞不同，NK细胞历来被认为是先天免疫细胞，可以在没有事先刺激的情况下直接杀死病原体，包括细菌、寄生虫和真菌，以及肿瘤细胞和病毒感染的细胞。这种特性是自然免疫力的一部分，因此得名自然杀伤细胞。然而，最近的研究提供了证据表明，NK细胞对以前遇到的病原体具有增强的反应，这一特性以前被归因于适应性免疫细胞，如T和B细胞。NK细胞表现出获得性免疫特性，其中先前的刺激导致刺激(抗原)特异性反应细胞的扩张和持久性，从而导致长期免疫并增强疗效。一些研究表明，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(丙型肝炎病毒)、乙肝病毒(乙肝病毒)、基孔肯雅病毒或HIV都具有抗原特异性的NK细胞记忆特性。这些研究中的大多数使用了完整的微生物。目前尚不清楚真菌，更具体地说，是否有生物体的任何可溶成分诱导NK细胞的适应性免疫记忆。我们以前的研究表明，NK细胞识别并直接杀死真菌，这需要NK细胞与真菌细胞接触并形成结合物。最近，我们证实了天然的细胞毒性受体NKp30是用于识别和介导抗真菌细胞毒性的NK细胞受体。最近，我们发现一种多糖，β-1，3-葡聚糖，真菌细胞壁的一种成分，也是许多细菌和谷物的成分，是NKp30(NAT)的结合伙伴。交警。正在修订中)。此外，我们还证明了可溶性β-1，3-葡聚糖可增强NK细胞对新生隐球菌和白色念珠菌的细胞毒作用，这两种真菌在环境中和许多疾病中都存在。β-1，3-葡聚糖促进NKp30的表达和释放杀灭微生物所需的细胞溶解分子，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获得性免疫反应。*在本提案中，我们将探讨“β-1，3-葡聚糖可通过与NKp30的特定结构域结合而触发NK细胞记忆”的假设。我们将首先分析NKp30与β-1，3-葡聚糖的相互作用，并确定NKp30和β-1，3-葡聚糖的结合部位。我们将探讨β-1，3-葡聚糖或其结合域在形成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.