Neuroimmune Biology of Natural Killer T Cells

自然杀伤 T 细胞的神经免疫生物学

• 批准号: RGPIN-2014-05284
• 负责人: Haeryfar, SMMansour
• 金额: $ 2.99万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=652800
• 关键词: Neuroimmune; Biology; Natural; Killer; Cells

The nervous and the immune system work towards a common goal - that is to preserve the homeostasis and to ensure the integrity of the organism in response to perceived threats. Although the existence of intricate crosstalk between the two systems has been long appreciated, our understanding of their interactions at cellular and molecular levels is far from clear. The main goal of the proposed research program is to further our understanding of how the nervous system controls immune responses mediated or regulated by natural killer T (NKT) cells. **NKT cells are a rare but remarkably potent subset of lymphocytes with several unusual characteristics. First, they express an invariant T cell receptor that can uniquely recognize glycolipid antigens such as alpha-galactosylceramide (alpha-GalCer). Second, they contain preformed mRNA encoding pro- and anti-inflammatory cytokines typified by interferon (IFN)-gamma and interleukin (IL)-4, respectively. As a result, they secrete enormous quantities of these cytokines very early in the course of an immune response. This results in transactivation of downstream effector cells (e.g., dendritic cells, macrophages, NK cells and conventional T lymphocytes) and dictates the course and nature of immune responses. The responsiveness of NKT cells is greatly influenced by the microenvironment in which these enigmatic cells are activated, which is likely to be shaped by various nervous system mediators. Our understanding of how NKT cells are controlled by such mediators is primitive. The proposed program will explore the effects of various nervous system mediators including but not limited to norepinephrine (NE), neuropeptide Y (NPY) and serotonin (aka. 5-hydroxytryptamine or 5-HT), on NKT cells' regulatory and effector functions. **Lymphoid organs are "hardwired" by sympathetic nerve termini and recent studies suggest that both innate and adaptive immune responses are controlled by the sympathetic nervous system (SNS). However, whether SNS mediators regulate NKT cells that in fact bridge these two arms of immunity is essentially unexplored. In the first cluster of projects defined in this application, we will investigate NKT cell functions in laboratory mice in which the peripheral SNS is rendered ineffective. In addition, we will explore the effects of the SNS mediators NE and NPY on mouse NKT cell responses ranging from alpha-GalCer-triggered proliferation to cytokine secretion and cell-mediated cytotoxicity. **5-HT is a classical neurotransmitter best known for its role in pain, appetite, sleep and mood. However, substantial evidence suggests that 5-HT may also play a role in modulation of host defense. Whether NKT cell responses are regulated by 5-HT is unknown and a subject of projects outlined in cluster II.**In longer-term projects (cluster III), we will perform comprehensive multi-gene profiling of neurotransmitter receptors constitutively present or inducible in NKT cells. This will likely lead to numerous projects revolving around the overall theme of the proposed program in neuroimmune biology of NKT cells. We will also explore the influence of nervous system mediators on NKT cell responses to glycolipid antigens other than alpha-GalCer, cytokines produced by other immune cells (e.g., IL-12 and IL-18), and bacterial superantigens. **Our studies will improve our understanding of NKT cell responses and their regulation at the neuroimmune interface. NKT cells' mode of recognition is evolutionarily conserved. Therefore, findings in mouse models are likely to be applicable to multiple mammalian species. The proposed program will enable the training of a future generation of scientists with a unique set of skills and expertise in an important, yet somewhat neglected area of biology.

神经系统和免疫系统朝着一个共同的目标工作，即保持体内平衡，并确保有机体的完整性，以应对感知到的威胁。虽然这两个系统之间存在复杂的串扰已经很久了，但我们对它们在细胞和分子水平上的相互作用的理解还远远不够清楚。该研究计划的主要目标是进一步了解神经系统如何控制自然杀伤T（NKT）细胞介导或调节的免疫反应。**NKT细胞是一种罕见但非常有效的淋巴细胞亚群，具有几种不寻常的特征。首先，它们表达一种不变的T细胞受体，可以独特地识别糖脂抗原，如α-半乳糖神经酰胺（α-GalCer）。第二，它们含有编码促炎细胞因子和抗炎细胞因子的预先形成的mRNA，所述促炎细胞因子和抗炎细胞因子分别以干扰素（IFN）-γ和白介素（IL）-4为代表。因此，它们在免疫应答过程的早期分泌大量的这些细胞因子。这导致下游效应细胞（例如，树突细胞、巨噬细胞、NK细胞和常规T淋巴细胞），并决定免疫应答的过程和性质。NKT细胞的反应性受到这些神秘细胞被激活的微环境的极大影响，这可能是由各种神经系统介质塑造的。我们对NKT细胞如何受这些介质控制的理解是原始的。拟议的计划将探讨各种神经系统介质的影响，包括但不限于去甲肾上腺素（NE），神经肽Y（NPY）和血清素（又名。5-羟色胺或5-HT）对NKT细胞的调节和效应子功能的影响。** 类神经器官是由交感神经末梢“硬连线”的，最近的研究表明先天性和适应性免疫反应都是由交感神经系统（SNS）控制的。然而，SNS介质是否调节NKT细胞，实际上桥接这两个免疫武器基本上是未探索的。在本申请中定义的第一组项目中，我们将研究外周SNS无效的实验室小鼠中的NKT细胞功能。此外，我们将探讨SNS介质NE和NPY对小鼠NKT细胞反应的影响，从α-GalCer触发的增殖到细胞因子分泌和细胞介导的细胞毒性。 **5-HT是一种经典的神经递质，以其在疼痛，食欲，睡眠和情绪中的作用而闻名。然而，大量证据表明，5-HT也可能在调节宿主防御中发挥作用。NKT细胞反应是否受5-HT调节尚不清楚，并且是第二组中概述的项目主题。**在长期项目（集群III）中，我们将对NKT细胞中组成性存在或可诱导的神经递质受体进行全面的多基因分析。这可能会导致围绕NKT细胞神经免疫生物学拟议计划的总体主题的许多项目。我们还将探索神经系统介质对NKT细胞对除α-GalCer以外的糖脂抗原、其他免疫细胞产生的细胞因子（例如，IL-12和IL-18）和细菌超抗原。 ** 我们的研究将提高我们对NKT细胞反应及其在神经免疫界面调节的理解。NKT细胞的识别模式在进化上是保守的。因此，小鼠模型中的发现可能适用于多种哺乳动物物种。拟议的计划将使未来一代的科学家与一套独特的技能和专业知识在一个重要的，但有点被忽视的生物学领域的培训。