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(MHC-I)分子为自身。正常的MHC-I水平不会 允许NK细胞攻击，但如果MHC-I在病理事件中下调，则NK细胞攻击。这个 申请人和他的实验室发现了针对MHC-I的Ly49受体家族 以及抑制NK细胞激活受体功能的分子，提供了一种分子 对失踪自我假说的解释。然而，自我缺失假说提供了一种 几乎没有观察到的预测，包括NK细胞在 缺乏MHC-I的宿主，而不是高反应性的NK细胞。这一点现在可以用更多的 申请人实验室的最新研究结果表明，Ly49受体具有第二个功能 许可或培养NK细胞自我MHC-I，从而产生适当的自我耐受的NK细胞。 关于缺失自我和NK细胞耐受性的其他悬而未决的问题仍然没有解决，例如 就好像所有的组织都受到MHC-I的保护，不受NK细胞的攻击，表达MHC-I的组织 授予许可，如果Ly49单独负责许可。在此，申请人提议 利用他的实验室最近培育的新小鼠来研究NK细胞的耐受性。在……里面 具体地说，这项建议的具体目的是研究：1)组织特异性和时间 缺失自我保护的几个方面；2)组织特异性诱导和维持许可的NK 细胞；3)Ly49s在自身MHC许可中的作用。这些研究将加强我们的 对自然杀伤细胞耐受性和自我缺失假说的理解。

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 (MHC-I) molecules as self. Normal levels of MHC-I do not allow NK cell attack but if MHC-I is down-regulated in a pathologic event, NK cells attack. The applicant and his laboratory discovered the Ly49 family of receptors specific for MHC-I molecules and that inhibit NK cell activation receptor function, providing a molecular explanation for the missing-self hypothesis. However, the missing-self hypothesis provides a few predictions that were not observed, including the hypo-responsiveness of NK cells in MHC-I-deficient hosts, rather than hyper-reactive NK cells. This can now be explained by more recent findings from the applicant's laboratory that the Ly49 receptors have a second function to license or educate NK cells to self-MHC-I, thereby generating appropriate self-tolerant NK cells. Other unresolved issues regarding missing-self and NK cell tolerance remain unresolved, such as if all tissues are protected by MHC-I from NK cell attack, the tissues expressing MHC-I that confer licensing, and if Ly49s are solely responsible for licensing. Herein the applicant proposes to study NK cell tolerance utilizing novel mice recently generated in his laboratory. In particular, the Specific Aims of this proposal are to study: 1) Tissue-specificity and temporal aspects of missing-self protection; 2) Tissue-specific induction and maintenance of licensed NK cells; and 3) Role of Ly49s in licensing by self-MHC. These studies will enhance our understanding of NK cell tolerance and the missing-self hypothesis.