Natural Killer Cell Tolerance to Self

摘要 自然杀伤(NK)细胞对自身的耐受性尽管广泛传播，但仍未完全了解 接受现在耳熟能详的“自我缺失”假设。作为…的指导原则 几十年来，它提出了NK细胞调查组织中普遍表达的主要 组织相容性复合体I类(MHCI)分子为自身。正常的MHCI水平不会 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。这个 申请者和他的实验室发现了针对靶细胞的Ly49受体家族 MHCI分子抑制NK细胞激活受体功能，为 理解自我缺失假说。然而，一些关于失踪自我的预测 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 低反应性NK细胞。现在，这可以用来自 申请人的实验室，抑制性Ly49受体有第二个功能许可或 培养NK细胞自我MHCI，使注册的NK细胞具有功能能力 激活受体。与此同时，还有其他问题。例如，在先前的研究中，申请人的实验室 表明不同的MHCI等位基因似乎对Ly49的功能有逐渐的影响， 提示信号强度解释了这些功能，可能是由于Ly49对 自身MHCI，部分与受体功能的变阻器模型有关，该模型一直不太好 学习。此外，MHCI影响Ly49的谱系，Ly49在斑驳的 每个NK细胞有一个以上的Ly49。来自申请人实验室的数据表明 自身MHCI特异性Ly49的信号影响另一种Ly49的表达，即自身MHCI- 特定的，可能为MHCI等位基因如何影响Ly49曲目提供解释。 最后，还不知道Ly49是如何授予许可的，例如抑制的可能性 受体可以直接发出许可表型的信号。在此，申请人提议学习 利用他的实验室最近培育的包括基因敲除在内的新型小鼠的NK细胞耐受性 在常规NK细胞上缺乏ALL Ly49表达的小鼠和本质上有 单个Ly49在所有NK细胞上的单克隆表达。因此，这一行动的具体目的是 建议研究：1)Ly49对自身MHCI的亲和力在许可、效应器抑制和 缺失自我；2)Ly49谱系的建立；3)抑制Ly49信号转导。因此， 这些研究将显著提高我们对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.