Natural Killer Cell Tolerance to Self

摘要 自然杀伤（NK）细胞对自身的耐受性尚未完全了解，尽管广泛传播 接受现在熟悉的“迷失自我”假说。作为指导原则， 几十年来，他们提出NK细胞可以检测组织中普遍表达的主要 组织相容性复合物I类（MHCI）分子作为自身。正常水平的MHCI不会 允许NK细胞攻击，但如果MHCI在病理事件中下调，则NK细胞攻击。的 申请人及其实验室发现了靶细胞特异性受体Ly 49家族 抑制NK细胞活化受体功能的MHCI分子，为 理解自我缺失假说然而，一些关于缺失自我的预测 没有观察到假设，例如MHCI缺陷宿主中的高反应性NK细胞，而是 低反应的NK细胞被发现。这可以用其他的研究结果来解释。 申请人的实验室证实抑制性Ly 49受体具有第二功能， 训练NK细胞自我MHCI，使得许可的NK细胞具有功能上的能力， 激活受体与此同时，其他问题。例如，在先前的研究中，申请人的实验室 显示不同的MHCI等位基因似乎对Ly 49功能具有渐进的影响， 这表明信号强度解释了这些功能，可能是由于Ly 49对这些功能的亲和力。 自我MHCI，部分与受体功能的变阻器模型有关， 研究了此外，MHCI影响Ly 49的所有组成部分，Ly 49在多种细胞中表达。 每个NK细胞有一个以上的Ly 49。申请人实验室的数据表明， 自身MHCI特异性Ly 49的信号传导影响另一种自身MHCI特异性Ly 49的表达。 特异性，可能提供了一个解释MHCI等位基因如何影响Ly 49库。 最后，Ly 49是如何授予许可的尚不清楚，例如，抑制性基因可能是一种基因。 受体可直接发信号通知许可表型。在此，申请人提议研究 NK细胞耐受性利用最近在他的实验室中产生的新型小鼠，包括敲除 在常规NK细胞上缺乏所有Ly 49表达的小鼠和基本上 在所有NK细胞上的单个Ly 49的单克隆表达。因此，本项目的具体目标 建议研究：1）Ly 49对自身MHCI的亲和力许可，效应子抑制， 缺失自身; 2）Ly 49库的建立;和3）抑制性Ly 49信号传导。因此，在本发明中， 这些研究将显著增强我们对NK细胞耐受性的理解。

Abstract Natural killer (NK) cell tolerance to self is incompletely understood despite wide-spread acceptance of the now familiar “missing-self” hypothesis. Serving as a guiding principle for several decades, it proposed that NK cells survey tissues for ubiquitously expressed major histocompatibility complex class I (MHCI) molecules as self. Normal levels of MHCI do not allow NK cell attack but if MHCI is down-regulated in a pathologic event, NK cells attack. The applicant and his laboratory discovered the Ly49 family of receptors specific for target cell MHCI molecules that inhibit NK cell activation receptor function, providing a basis for understanding the missing-self hypothesis. However, some predictions of the missing-self hypothesis were not observed, such as hyper-reactive NK cells in MHCI-deficient hosts, rather hypo-responsive NK cells were found. This can now be explained by other findings from the applicant's laboratory that the inhibitory Ly49 receptors have a second function to license or educate NK cells to self-MHCI, such that licensed NK cells have functionally competent activation receptors. Meanwhile, other issues. For example, in prior studies, the applicant's lab showed that different MHCI alleles appear to have graduated effects on Ly49 functions, suggesting signaling strength accounts for these functions, possibly due to Ly49 affinities for self-MHCI, in part related to the rheostat model for receptor function that has not been well studied. Moreover, MHCI affects the repertoire of Ly49s that are expressed in a variegated manner with more than one Ly49 per NK cell. Data from the applicant's laboratory suggest that signaling by a self-MHCI-specific Ly49 influences expression of another Ly49 that is self-MHCI- specific, potentially providing an explanation for how MHCI alleles affect the Ly49 repertoire. Finally, it is not known how the Ly49s confer licensing, such as the possibility that the inhibitory receptors may directly signal the licensing phenotype. Herein the applicant proposes to study NK cell tolerance utilizing novel mice recently generated in his laboratory, including knockout mice lacking all Ly49 expression on conventional NK cells and knockin mice with essentially monoclonal expression of a single Ly49 on all NK cells. Therefore, the Specific Aims of this proposal are to study: 1) Ly49 affinity for self-MHCI in licensing, effector inhibition and missing-self; 2) Establishment of the Ly49 repertoire; and 3) Inhibitory Ly49 signaling. Thus, these studies will markedly enhance our understanding of NK cell tolerance.