Mechanisms of co-stimulatory molecule expression in DCs

DC共刺激分子表达机制

• 批准号: 7161845
• 负责人: Amer Aziz Beg
• 金额: $ 35.81万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-15 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7161845
• 关键词: CD40 molecule; binding sites; chromatin immunoprecipitation; dendritic cells; gene deletion mutation; genetic regulation; genetic regulatory element; genetic transcription; genetically modified animals; immune response; immunogenetics; immunoregulation; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; macrophage; molecular cloning; nuclear factor kappa beta; posttranscriptional RNA processing; protein localization; site directed mutagenesis; transfection /expression vector

DESCRIPTION (provided by applicant): T cell activation requires a primary signal delivered by engagement of the T cell receptor (TCR) by MHC+ antigen complexes on antigen-presenting cells (APCs). In addition, a secondary signal delivered by the co-stimulatory molecules B7-1, B7-2 and CD40 on APCs, is also necessary for T cell activation. Amongst APCs, only dendritic cells (DCs) are thought to be capable of activating naive T lymphocytes. Microbial agents, such as lipopolysaccaride (LPS), are amongst the most important regulators of DC function. Engagement of Toll-like receptors (TLRs) by LPS and other microbial agents can lead to upregulation of cell surface expression of both MHC and co-stimulatory molecules on DCs, and the secretion of inflammatory cytokines. This process, often referred to as DC "maturation", is thought to be essential for initiating productive T cell activation. While many recent studies have addressed mechanisms involved in controlling MHC cell surface expression in DCs, little is known about mechanisms involved in regulating co-stimulatory molecule (CM) surface expression in these cells. The goal of studies proposed here is to help understand this key aspect of immune regulation. To this end, we will investigate LPS-induced molecular mechanisms that eventually determine cell surface expression levels of the CMs B7-1, B7-2 and CD40 in DCs. A better understanding of these crucial mechanisms may provide insights for modulating expression of these molecules in therapeutic settings. An additional key goal of studies proposed here is to define molecular mechanisms involved in determining functional specificity of macrophage and DC-induced responses, in particular, those pertaining to regulation of CM expression. The specific aims of this application are: (1) Transcriptional control of co-stimulatory molecule expression in DCs: role of NF-kB factors; (2) The role of post-transcriptional mechanisms in regulating co-stimulatory molecule cell surface expression in DCs; 3) Molecular mechanisms involved in determining functional specificity of macrophages and DCs: regulation of CM expression.

描述（由申请人提供）：T细胞激活需要通过MHC+抗原复合物在抗原呈递细胞（APC）上通过T细胞受体（TCR）传递的主要信号。此外，APC上的共刺激分子B7-1，B7-2和CD40传递的次级信号对于T细胞激活也是必需的。在APC中，只有树突状细胞（DC）被认为能够激活幼稚的T淋巴细胞。微生物剂，例如脂多菌（LPS），是直流功能最重要的调节剂之一。 LPS和其他微生物剂对Toll样受体（TLR）的参与可能导致DC上MHC和共刺激分子的细胞表面表达以及炎症细胞因子的分泌。这个过程通常称为直流“成熟”，被认为对于启动生产性T细胞激活至关重要。尽管许多最近的研究已经解决了控制DC中MHC细胞表面表达涉及的机制，但对于调节这些细胞中共刺激分子（CM）表面表达的机制知之甚少。这里提出的研究的目的是帮助了解免疫调节的这一关键方面。为此，我们将研究LPS诱导的分子机制，这些机制最终确定了DC中CMS B7-1，B7-2和CD40的细胞表面表达水平。对这些关键机制的更好理解可以为调节这些分子在治疗环境中的表达提供见解。这里提出的研究的另一个关键目标是定义涉及确定巨噬细胞功能特异性和DC诱导的响应的分子机制，特别是与CM表达有关的响应。该应用的具体目的是：（1）DCS中共刺激分子表达的转录控制：NF-KB因子的作用； （2）转录后机制在调节DC中的共刺激分子表面表达中的作用； 3）涉及确定巨噬细胞和DCS功能特异性的分子机制：CM表达的调节。