MHC Class l-independent NK Cell Regulation

MHC I 类独立的 NK 细胞调节

• 批准号: 6902244
• 负责人: KOHO IIZUKA
• 金额: $ 18.01万
• 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/6902244
• 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（申请人提供）：NK细胞无需事先致敏即可杀死肿瘤细胞，表明它们在肿瘤监测中发挥重要作用。它们在先天免疫和自身免疫中也发挥着重要作用。 NK细胞对杀伤的敏感性增强首先与靶细胞MHC I类分子表达降低有关，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，NK细胞就会从MHC I类对靶细胞的抑制影响中释放，导致靶细胞裂解。这种耐受机制由MHC I类特异性NK细胞解释 含有免疫受体酪氨酸抑制基序（ITIM）的抑制性受体。然而，MHC I 类表达本身并不能解释所有的 NK 抑制作用，并且已经假设了其他抑制性受体。申请人最近鉴定了小鼠MHC I类独立NK细胞抑制性受体及其配体Nkrpld和Clrb。与 MHC I 类分子和 MHC 特异性抑制不同 NK 细胞受体、以 Nkrpld 和 Clrb 为代表的这些受体和配体基因家族共定位于同一基因组区域，但与 MHC 特异性抑制性 NK 细胞受体相邻。对于这种新型 MHC I 类独立的 NK 细胞体内调节机制知之甚少。我们的长期目标是了解 NK 细胞调节和耐受的机制，特别是 MHC 类的机制 我独立。我们认为，我们的发现和拟议的实验计划的概念和基因组新颖性代表了“探索/发展研究资助奖（R21）”（PA-03-107）的理想契合。该应用的总体目标是了解 Nkrpl 和 Clr 家族成员的功能和表达。具体而言，具体目标是：1）阐明Clr表达机制。 2）确定角色 NK 细胞发育中的 Nkrpl/Clr 基因。这些研究对于我们了解先天免疫和改善 NK 细胞的治疗目的至关重要。