MHC Class l-independent NK Cell Regulation

MHC I 类独立的 NK 细胞调节

• 批准号: 7056172
• 负责人: KOHO IIZUKA
• 金额: $ 21.21万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7056172
• 关键词: MHC class I antigen; RNase protection assay; cell differentiation; cell growth regulation; cell mediated cytotoxicity; cell population study; flow cytometry; genetically modified animals; immune tolerance /unresponsiveness; immunogenetics; immunoregulation; laboratory mouse; lectin; ligands; major histocompatibility complex; natural killer cells; posttranslational modifications; protein localization; protein protein interaction; protein structure function; receptor expression; tyrosine

DESCRIPTION (provided by applicant): NK cells can kill tumor cells without prior sensitization, suggesting that they play important role in tumor surveillance. They also play an important role in innate immunity and autoimmunity. Enhanced susceptibility to killing by NK cells was first related to decreased expression of target cell MHC class I molecules, a finding that led to the "missing-self hypothesis. If MHC class I expression is downregulated, as in tumors or viral infection, NK cells are released from the inhibitory influence of MHC class I on the target cells resulting in target cell lysis. This tolerance mechanism is explained by MHC class I specific NK cell inhibitory receptors containing immunoreceptor tyrosine-based inhibitory motifs (ITIM). However, MHC Class I expression alone does not account for all NK inhibitory effects and other inhibitory receptors have been postulated. The applicant has recently identified a mouse MHC class I independent NK cell inhibitory receptor and its ligand, Nkrpld and Clrb. Unlike MHC class I molecules and MHC specific inhibitory NK cell receptors, these receptor and ligand gene families represented by Nkrpld and Clrb co-localize in the same genomic region, yet adjacent to MHC specific inhibitory NK cell receptors. Little is known in this novel MHC class I-independent NK cell regulation in vivo. Our longterm goal is to understand the mechanisms of NK cell regulation and tolerance, especially those that are MHC class I-independent. It is our opinion that the conceptual and genomic novelty of our findings and the proposed experimental plan represent an ideal fit for "Exploratory/Developmental Research Grant Award (R21)"(PA-03-107). The overall objective for this application is to understand the function and expression of Nkrpl and Clr family members. In particular, the specific aims are: 1) Elucidate the mechanisms of Clr expression. 2) Determine the role of Nkrpl/Clr genes in NK cell development. These studies are critical to our understanding of innate immunity and improving the manipulation of NK cells for therapeutic purposes.

描述（由申请方提供）：NK细胞可以在没有预先致敏的情况下杀死肿瘤细胞，表明它们在肿瘤监测中发挥重要作用。它们还在先天免疫和自身免疫中发挥重要作用。NK细胞杀伤敏感性的增强首先与靶细胞MHC I类分子表达的减少有关，这一发现导致了“自我缺失假说”。如果MHC I类表达下调，如在肿瘤或病毒感染中，则NK细胞从MHC I类对靶细胞的抑制性影响中释放，导致靶细胞裂解。这种耐受机制是由含有基于免疫受体酪氨酸的抑制基序（ITIM）的MHC I类特异性NK细胞抑制受体解释的。然而，单独的MHC I类表达不能解释所有的NK抑制作用，并且已经假定了其他抑制性受体。申请人最近鉴定了小鼠MHC I类非依赖性NK细胞抑制性受体及其配体Nkrpld和Clrb。与MHC I类分子和MHC特异性抑制性NK细胞受体不同，由Nkrpld和Clrb代表的这些受体和配体基因家族共定位于相同的基因组区域，但与MHC特异性抑制性NK细胞受体相邻。在这种新的MHC I类独立的NK细胞在体内的调节知之甚少。我们的长期目标是了解NK细胞调节和耐受的机制，特别是那些独立于MHC I类的机制。我们认为，我们的发现和拟议的实验计划的概念和基因组的新奇代表了一个理想的适合“探索/发展研究资助奖（R21）"（PA-03-107）。本申请的总体目标是了解Nkrpl和Clr家族成员的功能和表达。具体的目的是：1）阐明Clr的表达机制。2)确定Nkrpl/Clr基因在NK细胞发育中的作用。这些研究对于我们理解先天免疫和改善NK细胞的治疗目的至关重要。