Role of CD3delta in T-lymphocyte function

CD3delta 在 T 淋巴细胞功能中的作用

• 批准号: 7678510
• 负责人: BATU ERMAN
• 金额: $ 5.08万
• 依托单位: SABANCI UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7678510
• 关键词: Antibodies; Antigen-Presenting Cells; Binding; Biochemical; Biochemistry; Biological; Biological Assay; Biological Models; CD36 gene; Cell Line; Cells; Clinical; Complement; Complex; Computer Systems Development; Cytoplasmic Tail; Defect; Development; Docking; EMSA; Event; Experimental Models; Fluorescence Resonance Energy Transfer; Generations; Goals; High-Risk Cancer; Human; Immune; Immune system; Immunity; Immunocompromised Host; Immunologic Deficiency Syndromes; In Vitro; Incidence; Individual; Knockout Mice; Knowledge; Laboratories; Lead; Ligands; Link; Lymphocyte Function; Malignant Neoplasms; Mature T-Lymphocyte; Membrane; Modeling; Molecular; Mus; Patients; Peptide/MHC Complex; Play; Proteins; Receptor Signaling; Recruitment Activity; Reporter Genes; Role; Signal Transduction; Site; Staging; Stimulus; Surface; System; T-Cell Receptor; T-Lymphocyte; Testing; Transgenes; Transgenic Mice; Transgenic Organisms; Variant; Yeasts; crosslink; fight against; genetically modified cells; in vivo; mutant; programs; receptor; receptor expression; research study; thymocyte; tissue culture; tumor

DESCRIPTION (provided by applicant): T-lymphocyte deficient mice and immunocompromised humans have significantly higher incidence of various cancers, indicating that T lymphocytes play a critical role in tumor surveillance and rejection. Understanding how T cells develop and respond to T cell receptor (TCR) signals in a murine experimental model system will enhance our understanding of how T cells in immuno-competent humans perform surveillance against tumors. The TCR is a transmembrane receptor which has multiple signaling subunits. There is a gap in knowledge about the unique functions of individual signaling subunits of the TCR. The primary objective of his proposal is to understand how T lymphocytes respond to external stimuli when a key component of their TCR is absent. We have focused on the role of the CD3delta subunit in TCR signal transduction. CDSdelta deficiency has been observed in humans and results in an immunodeficiency syndrome. Unlike the other TCR subunits, CDSdelta is unique, in that not all TCR signaling events require this subunit. Our preliminary studies indicate that CD3delta deficient TCR signals are insufficient for the generation mature T cells in vivo, even though these receptors can signal if stimulated in vitro. This finding led to our central hypothesis that CDSdelta is responsible for the TCR to interact with CD4 or CDS co-receptors so that it can recognize MHC:peptide ligands on antigen presenting cells. We propose to use CDSdelta deficient cell lines grown in our tissue culture laboratory and murine models supplemented by CDSdelta transgenes to identify the molecular mechanism of this protein's contribution to TCR signal transduction. We will perform molecular biological and biochemical experiments that will lead to the cause of the defect observed during immune system development in the absence of CDSdelta. The objective of this proposal is to 1) attempt to overcome this developmental defect, 2) determine the mechanism of CDSdelta deficient TCR signals, 3) determine if CDSdelta interacts with co-receptor molecules on the surface of T lymphocytes. The genetically modified cell lines and mice created in this proposal will enable us to explore the function of ligand dependent and ligand independent signaling in T lymphocytes. A better understanding of CDSdelta deficient TCR signals will allow us to overcome the immunodeficiencies (and associated higher cancer risk) in patients that lack this protein.

描述（由申请人提供）：T淋巴细胞缺陷小鼠和免疫功能低下的人具有显著更高的各种癌症的发病率，表明T淋巴细胞在肿瘤监测和排斥中起关键作用。了解T细胞如何在小鼠实验模型系统中发育并响应T细胞受体（TCR）信号，将增强我们对免疫功能正常的人类中T细胞如何对肿瘤进行监视的理解。TCR是具有多个信号亚基的跨膜受体。关于TCR的单个信号亚基的独特功能的知识存在空白。他的建议的主要目标是了解T淋巴细胞如何响应外部刺激时，他们的TCR的关键组成部分是缺席。我们已经集中在TCR信号转导中的CD3 δ亚基的作用。CDSdelta缺陷已在人类中观察到并导致免疫缺陷综合征。与其他TCR亚基不同，CDSdelta是独特的，因为并非所有TCR信号传导事件都需要该亚基。我们的初步研究表明，CD3 δ缺陷型TCR信号不足以在体内产生成熟的T细胞，即使这些受体在体外刺激时也可以发出信号。这一发现导致了我们的中心假设，即CDSdelta负责TCR与CD4或CDS共受体相互作用，以便其能够识别抗原呈递细胞上的MHC：肽配体。我们建议使用在我们的组织培养实验室中生长的CDSdelta缺陷细胞系和补充CDSdelta转基因的小鼠模型来鉴定这种蛋白质对TCR信号转导的贡献的分子机制。我们将进行分子生物学和生物化学实验，这些实验将导致在缺乏CDSdelta的情况下免疫系统发育期间观察到的缺陷的原因。本提案的目的是1）试图克服这种发育缺陷，2）确定CDSdelta缺陷TCR信号的机制，3）确定CDSdelta是否与T淋巴细胞表面上的辅助受体分子相互作用。本研究所建立的转基因细胞系和小鼠将使我们能够探索T淋巴细胞中配体依赖性和配体非依赖性信号传导的功能。更好地了解CDSdelta缺陷TCR信号将使我们能够克服缺乏这种蛋白质的患者的免疫缺陷（以及相关的更高癌症风险）。