MECHANISM OF DIFFERENTIATION OF FUNCTION OF CD80 & CD86

两种共刺激分子(CD80和CD86)在专业APC膜上表达的生物学基础尚不清楚。许多结果表明，这两个分子都为T细胞提供了等价的共刺激信号。在体内和体外模型中，CD80和CD86在不同T细胞亚群激活中的不同作用也已被描述。我们发表的数据以及其他结果表明，CD86，而不是CD80，在DNA疫苗接种小鼠的过程中刺激细胞免疫反应。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？基于我们的结果，我们提出了几种机制来解释疫苗接种后的这些细胞反应？基于我们的结果，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和CD86的表达，而不是CD80和免疫原的表达，可能会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。第二，CD80和CD86可能激活不同的T细胞亚群。第三，CD80和CD86分子对受体的触发可能会向T细胞提供不同的信号。最后，APC表面的CD86而不是CD80的连接可以向这些细胞提供重要的信号，进而诱导某些分子的产生，如细胞因子/淋巴因子/趋化因子，这些分子对T细胞的激活是重要的。为了评估这些假设，我们建议使用DNA免疫作为一个模型系统来研究以下内容：1)CD80和CD86在MHC I类分子阳性和阴性肌肉组织微环境中的表达差异(即DNA接种部位免疫活性细胞的侵袭)。2)。免疫原与CD80/CD86表达载体联合免疫后，不同亚群的CTL(CD4+或C8+)和辅助性T细胞(Th1或Th2)被激活。3)。人CD86DNA与不同突变型CD86DNA联合免疫后，其功能区域/S参与了细胞免疫应答的增强。4)DNA疫苗免疫后共刺激分子和专业APC产生的细胞因子对T细胞活化的协同作用。5)。CD86和CD80在肌肉细胞和专业APC上连接后的基因差异表达。

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.