MHC Class l-independent NK Cell Regulation

描述（由申请人提供）：NK细胞无需事先致敏即可杀死肿瘤细胞，提示其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起着重要作用。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，NK细胞从MHC I类对靶细胞的抑制影响中释放出来，导致靶细胞裂解。这种耐受机制是由MHC I类特异性NK细胞抑制受体含有免疫受体酪氨酸基抑制基序（ITIM）来解释的。然而，MHC I类表达本身并不能解释所有NK抑制作用，并且已经假设了其他抑制受体。申请人最近鉴定了一种小鼠MHC I类独立NK细胞抑制受体及其配体Nkrpld和Clrb。与MHC I类分子和MHC特异性抑制NK细胞受体不同，这些受体和配体基因家族以Nkrpld和Clrb为代表，共定位于同一基因组区域，但与MHC特异性抑制NK细胞受体相邻。这种新型的MHC i类非依赖性NK细胞在体内的调节尚不清楚。我们的长期目标是了解NK细胞调节和耐受的机制，特别是那些与MHC i类无关的机制。我们认为，我们发现的概念和基因组的新颖性以及提出的实验计划代表了“探索性/发展性研究资助奖（R21）”（PA-03-107）的理想选择。该应用程序的总体目标是了解Nkrpl和Clr家族成员的功能和表达。具体目的是：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。这些研究对我们理解先天免疫和改善NK细胞的治疗目的至关重要。

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.