MECHANISM OF DIFFERENTIATION OF FUNCTION OF CD80 & CD86

CD80的功能分化机制

• 批准号: 6321827
• 负责人: Michael G Agadjanyan
• 金额: $ 26.13万
• 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/6321827
• 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.

专业 APC 膜上表达两种共刺激分子（CD80 和 CD86）的生物学原理尚不清楚。许多结果表明，这两种分子都能向 T 细胞提供等效的共刺激信号。在体内和体外模型中也描述了 CD80 和 CD86 在不同 T 细胞亚群激活中的不同作用。我们发表的数据以及其他结果表明，在小鼠 DNA 疫苗接种过程中，CD86 而不是 CD80 会刺激细胞免疫反应。重要的问题是为什么疫苗接种后增强 T 细胞反应需要 CD86 而不是 CD80？根据我们的结果，我们提出了几种机制来解释疫苗接种后的这些细胞反应？根据我们的结果，我们提出了几种机制来解释 CD80 和 CD86 分子之间的这些功能差异。首先，MHC I 类和 CD86（而不是 CD80）与免疫原的表达可能会诱导免疫活性细胞的局部侵袭，这对免疫反应的产生至关重要。其次，CD80 和 CD86 可能激活不同的 T 细胞亚群。第三，CD80和CD86分子受体的触发可能向T细胞提供不同的信号。最后，APC 表面上 CD86（而非 CD80）的连接可以向这些细胞提供重要信号，进而诱导某些分子的产生，例如细胞因子/淋巴因子/趋化因子，这些分子对于 T 细胞激活很重要。为了评估这些假设，我们建议使用 DNA 免疫作为模型系统来研究以下内容：1.) MHC I 类阳性或阴性肌肉组织微环境中 CD80 和 CD86 表达的差异效应（即 DNA 接种部位免疫活性细胞的侵袭）。 2）。使用免疫原和 CD80/CD86 表达质粒共同免疫后，CTL（CD4+ 或 C8+）和 T 辅助细胞（Th1 或 Th2）不同亚群的激活。 3）。人CD86分子的功能区参与与编码免疫原的DNA和不同的CD80/CD86突变分子共同免疫后细胞免疫应答的增强。 4）专业APC产生的共刺激分子和细胞因子对DNA疫苗接种后T细胞激活的协同作用。 5）。 CD86 与 CD80 连接后在肌肉细胞和专业 APC 上的基因差异表达。