Role of NKG2 Family Receptors in Regulating the Immune R

NKG2 家族受体在调节免疫 R 中的作用

• 批准号: 7313464
• 负责人: John E Coligan
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7313464
• 关键词: Role; NKG2; Family; Receptors; Regulating

Immune responses must be tightly regulated to avoid hypo-responsiveness on one hand or excessive inflammation and the development of autoimmunity (hyper-responsiveness) on the other. This balance is at least partially attained through the throttling of activating signals by inhibitory signals. This ideally leads to an adequate immune response against an invader without excessive and extended inflammatory signals that promote the development of autoimmunity. The CD94/NKG2 family of receptors is composed of members with activating or inhibitory potential. These receptors are expressed predominantly on NK cells and a subset of CD8+ T cells, and they have been shown to play an important role in regulating responses against infected and tumorigenic cells. Our studies explore all aspects of the biology of these receptors, including ligand and receptor interaction, signaling, membrane dynamics, and regulation of gene expression.Our current emphasis is to understand, at the cell biology and molecular levels, how the the CD94/NKGA inhibitory receptor inactivates signals generated by activation receptors in a dominating manner and by what mechanism this receptor traffics so as to maintain constant presence on the cell surface. This is an intriguing question because CD94/NKG2A is under constant exposure to ligand, which normally leads to receptor down regulation. If this were to happen, NK cells would become hyper-reactive leading to autoimmunity. We have preliminary data showing that CD94/NKG2A traffics by a novel mechanism. We also have preliminary data showing CD94/NKG2A inactivates activation receptors by inactivating key molecules necessary for transmission of activation siganals. It does this in a localized manner so that NK cells can still kill harmful bystander cells at sites where inhibitory signals are not generated. Understanding how CD94/NKG2A receptors signals and maintains cell surface expression are major areas of investigation. Furthermore, understanding the regulation of expression of the CD94 and NKG2A genes is particularly important, as expression of this inhibitory receptor on CD8 T cells has been shown to render these cells anergic. This has been demonstrated for HIV reactive CTLs. A second major area of interest are studies on the NKG2D activation/co-receptor that is expressed on NK and majority of CD8+ T cells. When NKG2D engages ligands (of which there are many) cell signaling events are transmitted through the adapters DAP10 and DAP12, which leads to cell activation events ending in target cell lysis/and or cytokine secretion. This receptor system has been shown to have potential impact in many diseases. Normal cells do not express NKG2D ligands, but cells under stress, i. e. infected and malignant, up-regulate NKG2D ligands making them vulnerable to attack by cells expressing NKG2D. On the negative side, inappropriate expression of NKG2D ligands has been shown to foster autoimmune diseases, such as diabetes, celiac disease, and preliminary evidence suggests a role for NKG2D in other autoimmune diseases. Also therapeutic NKG2D blockade may be of use in transplantation settings. Thus gaining knowledge of the mechanisms mediating the regulation of NKG2D protein and gene expression is an important aim of our research.

必须严格调节免疫反应，一方面避免反应低下，另一方面避免过度炎症和自身免疫（高反应）的发展。这种平衡至少部分是通过抑制信号对激活信号的节制来实现的。理想情况下，这会导致针对入侵者的充分免疫反应，而不会产生过多和延长的炎症信号，从而促进自身免疫的发展。 CD94/NKG2 受体家族由具有激活或抑制潜力的成员组成。这些受体主要在 NK 细胞和 CD8+ T 细胞的子集上表达，并且已被证明在调节针对感染细胞和致瘤细胞的反应中发挥重要作用。我们的研究探索了这些受体生物学的各个方面，包括配体和受体相互作用、信号传导、膜动力学和基因表达调控。我们当前的重点是在细胞生物学和分子水平上了解 CD94/NKGA 如何抑制性受体以主导方式灭活由激活受体产生的信号，以及该受体通过什么机制进行运输以维持在细胞表面上的恒定存在。这是一个有趣的问题，因为 CD94/NKG2A 持续暴露于配体，这通常会导致受体下调。如果发生这种情况，NK 细胞将变得过度反应，导致自身免疫。我们的初步数据表明 CD94/NKG2A 通过一种新颖的机制进行运输。我们还有初步数据显示 CD94/NKG2A 通过灭活激活信号传递所需的关键分子来灭活激活受体。它以局部方式做到这一点，以便 NK 细胞仍然可以在不产生抑制信号的部位杀死有害的旁观者细胞。了解 CD94/NKG2A 受体如何发出信号并维持细胞表面表达是研究的主要领域。此外，了解 CD94 和 NKG2A 基因表达的调节尤为重要，因为这种抑制性受体在 CD8 T 细胞上的表达已被证明会使这些细胞无反应性。这已在 HIV 反应性 CTL 中得到证实。 第二个主要兴趣领域是对 NK 和大多数 CD8+ T 细胞上表达的 NKG2D 激活/辅助受体的研究。当 NKG2D 与配体（有很多）结合时，细胞信号传导事件通过适配器 DAP10 和 DAP12 传递，从而导致细胞激活事件，最终导致靶细胞裂解/和/或细胞因子分泌。该受体系统已被证明对许多疾病具有潜在影响。正常细胞不表达 NKG2D 配体，但处于应激状态的细胞，即。 e. NKG2D 配体上调，使它们容易受到表达 NKG2D 的细胞的攻击。不利的一面是，NKG2D 配体的不当表达已被证明会促进自身免疫性疾病，例如糖尿病、乳糜泻，初步证据表明 NKG2D 在其他自身免疫性疾病中也发挥着作用。治疗性 NKG2D 阻断也可用于移植环境。因此，了解介导 NKG2D 蛋白和基因表达调节的机制是我们研究的一个重要目标。