Barouch Dan H, Santra Sampa, Tenner-Racz Klara, Racz Paul, Kuroda Marcelo J, Schmitz Joern E, Jackson Shawn S, Lifton Michelle A, Freed Dan C, Perry Helen C, Davies Mary-Ellen, Shiver John W, Letvin Norman L
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
J Immunol. 2002 Jan 15;168(2):562-8. doi: 10.4049/jimmunol.168.2.562.
Virus-specific CD4(+) T cell responses have been shown to play a critical role in controlling HIV-1 replication. Candidate HIV-1 vaccines should therefore elicit potent CD4(+) as well as CD8(+) T cell responses. In this report we investigate the ability of plasmid GM-CSF to augment CD4(+) T cell responses elicited by an HIV-1 gp120 DNA vaccine in mice. Coadministration of a plasmid expressing GM-CSF with the gp120 DNA vaccine led to only a marginal increase in gp120-specific splenocyte CD4(+) T cell responses. However, immunization with a bicistronic plasmid that coexpressed gp120 and GM-CSF under control of a single promoter led to a dramatic augmentation of vaccine-elicited CD4(+) T cell responses, as measured by both cellular proliferation and ELISPOT assays. This augmentation of CD4(+) T cell responses was selective, since vaccine-elicited Ab and CD8(+) T cell responses were not significantly changed by the addition of GM-CSF. A 100-fold lower dose of the gp120/GM-CSF bicistronic DNA vaccine was required to elicit detectable gp120-specific splenocyte proliferative responses compared with the monocistronic gp120 DNA vaccine. Consistent with these findings, i.m. injection of the gp120/GM-CSF bicistronic DNA vaccine evoked a more extensive cellular infiltrate at the site of inoculation than the monocistronic gp120 DNA vaccine. These results demonstrate that bicistronic DNA vaccines containing GM-CSF elicit remarkably potent CD4(+) T cell responses and suggest that optimal Th cell priming requires the precise temporal and spatial codelivery of Ag and GM-CSF.
病毒特异性CD4(+) T细胞应答已被证明在控制HIV-1复制中起关键作用。因此，候选HIV-1疫苗应引发强效的CD4(+)以及CD8(+) T细胞应答。在本报告中，我们研究了质粒GM-CSF增强HIV-1 gp120 DNA疫苗在小鼠中引发的CD4(+) T细胞应答的能力。将表达GM-CSF的质粒与gp120 DNA疫苗共同给药仅导致gp120特异性脾细胞CD4(+) T细胞应答略有增加。然而，用在单个启动子控制下共表达gp120和GM-CSF的双顺反子质粒免疫导致疫苗引发的CD4(+) T细胞应答显著增强，这通过细胞增殖和ELISPOT测定来衡量。CD4(+) T细胞应答的这种增强是选择性的，因为添加GM-CSF后疫苗引发的抗体和CD8(+) T细胞应答没有显著变化。与单顺反子gp120 DNA疫苗相比，引发可检测到的gp120特异性脾细胞增殖应答需要低100倍剂量的gp120/GM-CSF双顺反子DNA疫苗。与这些发现一致，与单顺反子gp120 DNA疫苗相比，肌肉注射gp120/GM-CSF双顺反子DNA疫苗在接种部位引起更广泛的细胞浸润。这些结果表明，含有GM-CSF的双顺反子DNA疫苗可引发非常强效的CD4(+) T细胞应答，并表明最佳的Th细胞启动需要抗原和GM-CSF精确的时间和空间共递送。
