Role of NKG2 Family Receptors in Regulating the Immune Response

NKG2 家族受体在调节免疫反应中的作用

基本信息

批准号：
7592317
负责人：
John E Coligan
金额：
$ 99.7万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/7592317
关键词：
Actins Allergic Reaction Anabolism Antigens Autoimmune Diseases Autoimmune Process Autoimmunity Biochemical Biology CD8B1 gene Celiac Disease Cell surface Cells Cellular biology Chromosome Pairing Complex Cytoskeleton Data Development Diabetes Mellitus Disease Disruption Distal Endocytosis Equilibrium Exclusion Exposure to Family Fostering Gene Expression Gene Expression Regulation Genes Goals Guanine Nucleotide Exchange Factors HIV Hand Human ITIM IgE Immune Immune response Inflammation Inflammatory Inhibitory Synapse KLRD1 gene Ligands Light Link Malignant - descriptor Mediating Mediator of activation protein Membrane Membrane Microdomains Microfilaments Molecular NK Cell Activation Natural Killer Cells Normal Cell Phosphorylation Play Process Protein Dephosphorylation Protein Tyrosine Phosphatase Proteins Reaction Receptor Activation Receptor Signaling Role Side Signal Transduction Stress Surface Synapses T-Lymphocyte immunological synapse mast cell member prevent receptor response trafficking tumorigenic

项目摘要

Immune responses must be tightly regulated to avoid hyporesponsiveness on one hand or excessive inflammation and the development of autoimmunity (hyperresponsiveness) 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 CD94NKG2 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 CD94NKGA 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. The exact means by which inhibitory signals obviate activation signals in immune cells are not totally elucidated. Human CD94NKG2A is an ITIM containing inhibitory receptor expressed by NK cells and some CD8 T cells that recognizes HLAE. We showed that the engagement of this receptor prevents NK cell activation by disruption of the actin network and exclusion of lipid rafts at the point of contact with its ligand (inhibitory NK cell immunological synapse, iNKIS). CD94NKG2A engagement leads to recruitment and activation of src homology 2 domain bearing tyrosine phosphatase 1. This likely explains the observed dephosphorylation of guanine nucleotide exchange factor and regulator of actin, Vav1, as well as ezrinradixinmoesin proteins that connect actin filaments to membrane structures. In contrast, NK cell activation by NKG2D induced Vav1 and ezrinradixinmoesin phosphorylation. Thus, CD94NKG2A prevents actin dependent recruitment of raft associated activation receptors complexes to the activating synapse. These data indicate that the lipid rafts exclusion at the iNKIS is an active process which requires an intact cytoskeleton to maintain lipid rafts outside the inhibitory synapse. The net effect is to maintain an inhibitory state in the proximity of the iNKIS, while allowing the formation of activation synapse at distal points within the same NK cell.

必须严格调节免疫反应，以避免一只手或过度炎症以及另一方面自身免疫性（过度反应性）的发展。这种平衡至少通过抑制信号的激活信号进行部分实现。理想情况下，这会导致对入侵者的适当免疫反应，而没有过度和扩展的炎症信号，从而促进自身免疫的发展。 CD94NKG2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，并且已证明它们在调节针对感染和肿瘤细胞的反应中起着重要作用。我们的研究探索了这些受体生物学的各个方面，包括配体和受体的相互作用，信号传导，膜动力学以及基因表达的调节。我们的当前重点是在细胞生物学和分子水平上理解CD94NKGA抑制受体失活的信号是如何通过一种受体来培养这种受体的受体，并通过这种机制来维持这种受体的传播。抑制信号避免免疫细胞中激活信号的确切均值未完全阐明。人CD94NKG2A是一种ITIM，含有由NK细胞表达的抑制受体和一些识别HLAE的CD8 T细胞。我们表明，该受体的参与度通过破坏肌动蛋白网络的破坏和与其配体接触时的排除（抑制性NK细胞免疫突触，Inkis）来防止NK细胞的激活。 CD94NKG2A参与导致SRC同源性的募集和激活2轴承酪氨酸磷酸酶1。这可能解释了观察到的鸟嘌呤核苷酸交换因子和肌动蛋白的调节因子的去磷酸化，VAV1的调节因子，VAV1的调节剂，以及ezrinradixinmoesinmoesinmoesinmoesinmoesinmoes intecin ins contectin conternixinmoes inte niment蛋白蛋白与粘液蛋白结构的结构。相反，NKG2D诱导VAV1和Ezrinradixinmoesin磷酸化的NK细胞激活。因此，CD94NKG2A阻止了肌动蛋白依赖性募集筏相关的激活受体复合物与激活突触的络合。这些数据表明，Inkis处的脂质筏是一个活跃的过程，它需要完整的细胞骨架以维持抑制性突触外的脂质筏。净效应是在Inkis的接近度保持抑制状态，同时允许在同一NK细胞内远端的激活突触形成。