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（MHC-I）分子作为自身。正常水平的MHC-I不 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。的 申请人及其实验室发现了MHC-I特异性受体Ly 49家族 分子，并抑制NK细胞活化受体功能，提供了一种分子 对自我缺失假说的解释然而，缺失自我假说提供了一个 一些预测没有观察到，包括NK细胞的低反应性， MHC-I缺陷宿主，而不是高反应性NK细胞。这可以用更多的解释来解释。 申请人的实验室最近发现Ly 49受体具有第二种功能， 许可或训练NK细胞自我-MHC-I，从而产生适当的自我耐受NK细胞。 其他未解决的问题，如自我缺失和NK细胞耐受性仍然没有得到解决， 似乎所有组织都受到MHC-I的保护，不受NK细胞的攻击，表达MHC-I的组织， 授予许可证，如果Ly 49只负责许可证。在此，申请人提出， 利用他实验室最近培育的新型小鼠研究NK细胞耐受性。在 具体而言，本提案的具体目的是研究：1）组织特异性和时间 缺失自我保护的方面; 2）组织特异性诱导和维持许可的NK 细胞;和3）Ly 49在通过自身MHC许可中的作用。这些研究将加强我们的 对NK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.