Role of NKG2 Family Receptors in Regulating the Immune R

必须严格调节免疫反应，一方面避免低反应性，另一方面避免过度炎症和自身免疫（高反应性）的发展。这种平衡至少部分是通过抑制信号对激活信号的抑制来实现的。理想情况下，这导致了对入侵者的充分免疫反应，没有过度和延长的炎症信号，促进自身免疫的发展。CD94/NKG2受体家族由具有激活或抑制潜能的成员组成。这些受体主要在NK细胞和CD8+ T细胞亚群上表达，它们已被证明在调节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。我们目前的重点是在细胞生物学和分子水平上了解CD94/NKGA抑制受体如何以主导方式失活激活受体产生的信号，以及该受体通过何种机制运输以保持在细胞表面的持续存在。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细胞会变得高度反应，导致自身免疫。我们有初步的数据显示CD94/NKG2A通过一种新的机制进行交通。我们也有初步数据显示CD94/NKG2A通过失活激活信号传递所需的关键分子来失活激活受体。它以一种局部的方式做到这一点，因此NK细胞仍然可以在没有产生抑制信号的地方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基因的表达调控尤为重要，因为这种抑制受体在CD8 T细胞上的表达已被证明会使这些细胞失能。这已经在HIV反应性ctl中得到证实。

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.