Protective CD8 T cell immunity triggered by CpG-protein conjugates competes with the efficacy of live vaccines
Protective CD8 T cell immunity triggered by CpG-protein conjugates competes with the efficacy of live vaccines
复制标题
DOI：
10.4049/jimmunol.174.7.4373
复制
发表时间：
2005-04-01
影响因子：
4.4
通讯作者：
Huster, KM
中科院分区：
文献类型：
--
作者：
Heit, A;Schmitz, F;Huster, KM
与感染性（活）疫苗相反，基于亚单位Ag的疫苗在引发保护性CD 8 T细胞应答方面是出了名的差，推测是因为亚单位Ag变得不足以被树突状细胞（DC）交叉呈递，并且因为后者需要被激活以获得交叉引发的能力。在这项研究中，我们表明，CpG-Ag复合物克服了这些限制。与CpG-DNA共价连接的OVA（CpG-OVA复合物）一旦通过DNA受体介导的内吞作用被DC有效内化，就被易位到溶酶体相关膜蛋白1（LAMP-1）阳性的内体-溶酶体区室，最近显示出交叉呈递的能力。同时，CpG-OVA复合物负载的DC被激活并获得专业APC的特征。在体内，单次s.c.剂量的CpG-OVA复合物（10 μ g蛋白质）诱导Ag特异性CD 8 T细胞的初级和次级克隆扩增/收缩，其动力学与活疫苗相似;实例包括经遗传工程改造以产生OVA的单核细胞增生李斯特菌（LM-OVA）和分析的两种基于病毒载体的OVA疫苗。有趣的是，CpG-OVA复合物诱导的Ag特异性记忆CD 8 T细胞的百分比与LM-OVA感染几乎相同。用CpG-OVA复合物的单剂量疫苗接种保护小鼠免受致死剂量的LM-OVA。这些数据强调了由CpG-OVA复合物介导的先天性和特异性免疫的联合触发所赋予的协同作用可能是通过基于亚单位Ag的合成疫苗启动基于CD 8 T细胞的免疫保护的关键。
In contrast to infectious (live) vaccines are those based on subunit Ag that are notoriously poor in eliciting protective CD8 T cell responses, presumabily because subunit Ags become insufficiently cross-presented by dendritic cells (DCs) and because the latter need to be activated to acquire competence for cross-priming. In this study, we show that CpG-Ag complexes overcome these limitations. OVA covalently linked to CpG-DNA (CpG-OVA complex), once it is efficiently internalized by DCs via DNA receptor-mediated endocytosis, is translocated to lysosomal-associated membrane protein 1 (LAMP-1)-positive endosomal-lysosomal compartments recently shown to display competence for cross-presentation. In parallel, CpG-OVA complex loaded DCs become activated and acquire characteristics of professional APCs. In vivo, a single s.c. dose of CpG-OVA complex (10 mu g of protein) induces primary and secondary clonal expansion/contraction of Ag-specific CD8 T cells similar in kinetics to live vaccines; examples including Listeria monocytogenes genetically engineered to produce OVA (LM-OVA) and two viral vector-based OVA vaccines analyzed. Interestingly, CpG-OVA complex induced almost equal percentages of Ag-specific memory CD8 T cells as did infection with LM-OVA. A single dose vaccination with CpG-OVA complex protected mice against lethal doses of LM-OVA. These data underscore that the synergy imparted by CpG-OVA complex-mediated combined triggering of innate and specific immunity might be key to initiate CD8 T cell-based immunoprotection by synthetic vaccines based on subunit Ag.