Role of CD3delta in T-lymphocyte function

描述(申请人提供)：T淋巴细胞缺陷小鼠和免疫功能低下的人类在各种癌症中的发病率显著较高，表明T淋巴细胞在肿瘤监测和排斥反应中发挥着关键作用。在小鼠实验模型系统中了解T细胞是如何发展和响应T细胞受体(TCR)信号的，将有助于我们理解免疫能力强的人的T细胞是如何进行肿瘤监视的。TCR是一种跨膜受体，具有多个信号亚基。关于TCR的各个信号亚基的独特功能，人们的认识还存在差距。他的建议的主要目标是了解当T淋巴细胞TCR的关键成分缺失时，T淋巴细胞如何对外部刺激做出反应。我们重点研究了CD3Delta亚单位在TCR信号转导中的作用。在人类中观察到CDSDelta缺乏症，并导致免疫缺陷综合征。与其他TCR亚基不同，CDSDelta是独一无二的，因为并不是所有的TCR信号事件都需要这个亚基。我们的初步研究表明，CD3Delta缺陷的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可以发出信号。这一发现导致了我们的中心假设，CDSDelta负责TCR与CD4或CDS共受体相互作用，以便它能够识别抗原提呈细胞上的MHC：肽配体。我们建议使用我们组织培养实验室培养的CDSDelta缺陷细胞系和CDSDelta转基因补充的小鼠模型来确定该蛋白对TCR信号转导的作用的分子机制。我们将进行分子生物学和生物化学实验，这些实验将导致在没有CDSDelta的情况下免疫系统发育过程中观察到的缺陷的原因。本研究的目的是：1)试图克服这一发育缺陷；2)确定CDSDelta缺失TCR信号的机制；3)确定CDSDelta是否与T淋巴细胞表面的辅受体分子相互作用。在这个方案中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和配体非依赖信号的功能。更好地了解CDSDelta缺陷的TCR信号将使我们能够克服缺乏这种蛋白的患者的免疫缺陷(以及相关的更高的癌症风险)。

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.