MECHANISM OF DIFFERENTIATION OF FUNCTION OF CD80 & CD86

CD80的功能分化机制

• 批准号: 6349888
• 负责人: Michael G Agadjanyan
• 金额: $ 30.64万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-01 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349888
• 关键词: CD antigens; MHC class I antigen; antigen presenting cell; biological signal transduction; cytotoxic T lymphocyte; enzyme linked immunosorbent assay; gene expression; genetically modified animals; helper T lymphocyte; immunization; immunocytochemistry; laboratory mouse; leukocyte activation /transformation; plasmids; protein structure function; surface antigens; transfection; vector vaccine; virus genetics

The biological rationale for the expression of two co-stimulatory molecules (CD80 and CD86) on the membrane of professional APC is not clear. Many results demonstrate that both molecules provide equivalent co-stimulatory signals to T-cells. Different roles for CD80 and CD86 in the activation of distinct subpopulations of T-cells have also been described in both in vivo and in vitro models. Our published data along with other results indicate that CD86, but not CD80, stimulates cellular immune responses during DNA vaccination of mice. The important question is why CD86, but not CD80 is required for augmentation of T-cell response after vaccination? Based on our results we suggest several mechanisms to explain these cell responses after vaccination? Based on our results we suggest several mechanisms to explain these functional differences between CD80 and CD86 molecules. First, expression of MHC class I and CD86, but not CD80 along with immunogen may induce local invasion of immunocompetent cells crucial for generation of immune responses. Second, CD80 and CD86 may activate different subpopulations of T-cells. Third, the triggering of receptors with CD80 and CD86 molecules may supply different signals to T-cells. Finally, the ligation of CD86, but not CD80 on the surface of APC could provide important signal to these cells and in turn induce production of certain molecules such as cytokines/lymphokines/chemokines, which are important for T cell activation. To evaluate these hypotheses we propose using DNA immunization as a model system to investigate the following: 1.) The differential effects of CD80 and CD86 expression in the microenvironment of MHC class I positive or negative muscle tissues (i.e. the invasion of immunocompetent cells at the site of DNA inoculation). 2). The activation of different subsets of CTL (CD4+ or C8+) and T helper cells (Th1 or Th2) after co-immunization with immunogen and CD80/CD86 expressing plasmids. 3). The functional region/s of human CD86 molecule involved in enhancement of cellular immune responses after co-immunization with DNA encoding immunogen and different CD80/CD86 mutant molecules. 4) The synergistic effect of co- stimulatory molecules and cytokines produced by professional APC, on T-cell activation after DNA vaccination. 5). The differential expression of genes after ligation of CD86 versus CD80 on muscle cells and professional APC.

在专职APC的膜上表达两种共刺激分子（CD 80和CD 86）的生物学原理尚不清楚。许多结果表明，这两种分子提供等效的共刺激信号的T细胞。在体内和体外模型中也描述了CD 80和CD 86在不同T细胞亚群活化中的不同作用。我们发表的数据沿着其他结果表明，在小鼠DNA疫苗接种期间，CD 86而不是CD 80刺激细胞免疫应答。重要的问题是为什么CD 86，而不是CD 80是疫苗接种后T细胞反应增强所必需的？根据我们的研究结果，我们提出了几种机制来解释这些细胞接种疫苗后的反应？基于我们的研究结果，我们提出了几种机制来解释这些CD 80和CD 86分子之间的功能差异。首先，I类MHC和CD 86的表达，而不是CD 80沿着免疫原的表达，可能诱导对产生免疫应答至关重要的免疫活性细胞的局部侵袭。其次，CD 80和CD 86可以激活不同的T细胞亚群。第三，CD 80和CD 86分子对受体的触发可能向T细胞提供不同的信号。最后，APC表面上的CD 86而不是CD 80的连接可以向这些细胞提供重要的信号，并且反过来诱导某些分子如细胞因子/淋巴因子/趋化因子的产生，这些分子对于T细胞活化是重要的。为了评估这些假设，我们提出使用DNA免疫作为模型系统来研究以下内容：1. CD 80和CD 86表达在MHC I类阳性或阴性肌肉组织的微环境中的差异效应（即免疫活性细胞在DNA接种部位的侵入）。2）。免疫原和CD 80/CD 86表达质粒联合免疫后不同亚群的CTL（CD 4+或C8+）和辅助性T细胞（Th 1或Th 2）的活化。3）。人CD 86分子的功能区参与免疫原编码DNA与不同CD 80/CD 86突变体分子共免疫后细胞免疫应答的增强。4)由专职APC产生的共刺激分子和细胞因子对DNA疫苗接种后T细胞活化的协同作用。5）。肌细胞和专职APC上CD 86与CD 80连接后基因的差异表达。