Plasmid DNA encoding CCR7 ligands compensate for dysfunctional CD8+ T cell responses by effects on dendritic cells
Plasmid DNA encoding CCR7 ligands compensate for dysfunctional CD8+ T cell responses by effects on dendritic cells
复制标题
DOI：
10.4049/jimmunol.167.7.3592
复制
发表时间：
2001-10-01
影响因子：
4.4
通讯作者：
Rouse, BT
中科院分区：
文献类型：
--
作者：
Eo, SK;Kumaraguru, U;Rouse, BT
缺乏淋巴结和脾脏结构紊乱的α-光毒素缺陷（LT α（-/-））小鼠在HSV感染后产生功能失调的CD8（+）T细胞，并容易死于疱疹性脑炎。通过MHC I类四聚体染色测量，这些小鼠确实产生了明显正常的肽特异性CD8（+）T细胞应答，但大多数细胞不能成为细胞毒性细胞或表达肽诱导的IFN-γ产生。在本研究中，我们证明了LT α（-/-）小鼠中CD8（+）T细胞的功能缺陷可以通过在HSV感染前给予编码CCR7配体的质粒DNA而在很大程度上得到纠正。治疗的突变小鼠产生了增加的肽特异性细胞毒性反应，增加了能够产生IFN-γ的CD8（+）T细胞的数量，以及改善了对HSV攻击的抵抗力。趋化因子治疗的纠正效果似乎是由于改善树突状细胞介导的Ag呈递。因此，治疗的主要结果是CCR7配体治疗的LT α（-/-）小鼠中脾树突状细胞数量增加，这些脾细胞群在体外显示出改善的APC活性。我们的研究结果证明，CD8（+）T细胞的功能缺陷可以得到纠正，并表明编码适当趋化因子的质粒载体的价值，以实现这种免疫治疗。
Lymphotoxin alpha -deficient (LT alpha (-/-)) mice, which lack lymph nodes and possess a disorganized spleen, develop dysfunctional CD8(+) T cells upon HSV infection and readily succumb to herpes encephalitis. Such mice do develop apparently normal peptide-specific CD8(+) T cell responses, as measured by MHC class I tetramer staining, but the majority of cells fail to become cytotoxic or express peptide-induced IFN-gamma production. In the present study, we demonstrate that functional defects of CD8(+) T cells in LT alpha (-/-) mice can be largely rectified by the administration of plasmid DNA encoding CCR7 ligands before HSV infection. Treated mutant mice developed increased peptide-specific cytotoxic responses, enhanced numbers of CD8(+) T cells capable of producing IFN-gamma, as well as improved resistance to HSV challenge. The corrective effect of chemokine treatment appeared to result from improved dendritic cell-mediated Ag presentation. Thus, a major consequence of the treatment was an increase in splenic dendritic cell number in CCR7 ligand-treated LT alpha (-/-) mice with such splenocyte populations showing improved APC activity in vitro. Our results document that functional defects of CD8(+) T cells can be corrected, and indicate the value of plasmid vector encoding appropriate chemokines to achieve such immunotherapy.