Natural Killer Cell Tolerance to Self

自然杀伤细胞对自身的耐受性

• 批准号: 9433623
• 负责人: Wayne M. Yokoyama
• 金额: $ 52.57万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9433623
• 关键词: Address; Adoptive Cell Transfers; Alleles; CRISPR/Cas technology; Cells; Complex; Event; Evolution; Family; Gene Cluster; Gene Family; Genes; Genetic Polymorphism; Human; Immune; Impairment; Inflammatory; Laboratories; Lead; Lectin; Licensing; MHC Class I Genes; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Molecular; Mus; Mutant Strains Mice; NK Cell Activation; Natural Killer Cells; Normal Cell; Normal tissue morphology; Pathologic; Production; Receptor Activation; Receptor Cell; Regulation; Role; Self Tolerance; Site; Specificity; Surveys; Testing; Thinking; Tissues; autoreactivity; beta-2 Microglobulin; cytokine; genome editing; killer immunoglobulin-like receptor; novel; receptor; receptor function; response; tumor

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.

抽象的 自然杀手（NK）对自我的耐受性不完全理解目的地广泛 接受现在熟悉的“失踪”假设。作为指导原则 几十年来，它提出NK细胞对无处不在的组织进行了调查 组织相容性复合物I类（MHC-I）分子作为自我。正常水平的MHC-I不 允许NK细胞攻击，但如果在病理事件中下调MHC-I，则NK细胞攻击。这 申请人及其实验室发现了特定于MHC-I的LY49接收器家族 分子并抑制NK细胞活化受体功能，提供分子 解释缺失的假设。但是，缺失的假设提供了 很少有未观察到的预测，包括NK细胞中的低反应性 MHC-I缺陷宿主，而不是过度反应的NK细胞。现在可以用更多 申请人实验室的最新发现，LY49受体具有第二个功能 许可或对NK细胞进行自我MHC-I的许可，从而产生适当的自我耐受性NK细胞。 关于失踪和NK细胞耐受性的其他未解决的问题仍未解决，这样 好像所有组织都受到NK细胞攻击的MHC-I保护，表达MHC-I的组织表明 会议许可，如果LY49是一个完全负责许可的。此处的申请人提案 使用最近在他的实验室中产生的新小鼠研究NK细胞耐受性。在 特别是，该提案的具体目的是研究：1）组织特异性和临时性 缺失自我保护的各个方面； 2）授权NK的组织特异性诱导和维护 细胞； 3）LY49在自我MHC许可中的作用。这些研究将增强我们的 了解NK细胞耐受性和缺失的假设。