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.

摘要