Natural Killer Cell Tolerance to Self
自然杀伤细胞对自身的耐受性
基本信息
- 批准号:9433623
- 负责人:
- 金额:$ 52.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAdoptive Cell TransfersAllelesCRISPR/Cas technologyCellsComplexEventEvolutionFamilyGene ClusterGene FamilyGenesGenetic PolymorphismHumanImmuneImpairmentInflammatoryLaboratoriesLeadLectinLicensingMHC Class I GenesMaintenanceMajor Histocompatibility ComplexMalignant NeoplasmsMediatingMolecularMusMutant Strains MiceNK Cell ActivationNatural Killer CellsNormal CellNormal tissue morphologyPathologicProductionReceptor ActivationReceptor CellRegulationRoleSelf ToleranceSiteSpecificitySurveysTestingThinkingTissuesautoreactivitybeta-2 Microglobulincytokinegenome editingkiller immunoglobulin-like receptornovelreceptorreceptor functionresponsetumor
项目摘要
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
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,
许可或教育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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Wayne M. Yokoyama其他文献
Immune functions encoded by the natural killer gene complex
自然杀伤基因复合体编码的免疫功能
- DOI:
10.1038/nri1055 - 发表时间:
2003-04-01 - 期刊:
- 影响因子:60.900
- 作者:
Wayne M. Yokoyama;Beatrice F. M. Plougastel - 通讯作者:
Beatrice F. M. Plougastel
The mother-child union: the case of missing-self and protection of the fetus.
母子结合:自我缺失与胎儿保护案例
- DOI:
- 发表时间:
1997 - 期刊:
- 影响因子:11.1
- 作者:
Wayne M. Yokoyama - 通讯作者:
Wayne M. Yokoyama
Expression of a single inhibitory Ly49 receptor is sufficient to license NK cells for effector functions
单一抑制性 Ly49 受体的表达足以许可 NK 细胞发挥效应功能
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Sytse J. Piersma;Shasha Li;Pamela Wong;Michael D. Bern;Jennifer Poursine‐Laurent;Liping Yang;D. L. Beckman;Bijal A. Parikh;Wayne M. Yokoyama - 通讯作者:
Wayne M. Yokoyama
Structural basis of MHCI antigen presentation sabotage by cowpox CPXV203
- DOI:
10.1016/j.molimm.2012.02.034 - 发表时间:
2012-05-01 - 期刊:
- 影响因子:
- 作者:
William H. McCoy;Xiaoli Wang;Wayne M. Yokoyama;Ted H. Hansen;Daved Fremont - 通讯作者:
Daved Fremont
Catch us if you can
如果你能就抓住我们
- DOI:
10.1038/419679a - 发表时间:
2002-10-17 - 期刊:
- 影响因子:48.500
- 作者:
Wayne M. Yokoyama - 通讯作者:
Wayne M. Yokoyama
Wayne M. Yokoyama的其他文献
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{{ truncateString('Wayne M. Yokoyama', 18)}}的其他基金
Infectious Disease/Immunology Stimulating Access to Research in Residency (ID/IMM StARR) Program at Washington University
华盛顿大学传染病/免疫学促进住院医师研究 (ID/IMM StARR) 项目
- 批准号:
10592699 - 财政年份:2023
- 资助金额:
$ 52.57万 - 项目类别:
ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY
妊娠期子宫自然杀伤细胞的起源和功能
- 批准号:
10451584 - 财政年份:2018
- 资助金额:
$ 52.57万 - 项目类别:
ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY
妊娠期子宫自然杀伤细胞的起源和功能
- 批准号:
10216997 - 财政年份:2018
- 资助金额:
$ 52.57万 - 项目类别:
ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY
妊娠期子宫自然杀伤细胞的起源和功能
- 批准号:
9980287 - 财政年份:2018
- 资助金额:
$ 52.57万 - 项目类别:
ORIGINS AND FUNCTIONS OF UTERINE NATURAL KILLER CELLS IN PREGNANCY
妊娠期子宫自然杀伤细胞的起源和功能
- 批准号:
9762839 - 财政年份:2018
- 资助金额:
$ 52.57万 - 项目类别:
Natural Killer Cell Control of Murine Cytomegalovirus Infection
自然杀伤细胞控制鼠巨细胞病毒感染
- 批准号:
10444730 - 财政年份:2017
- 资助金额:
$ 52.57万 - 项目类别: