Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets
Protective T cell immunity in mice following protein-TLR7/8 agonist-conjugate immunization requires aggregation, type I IFN, and multiple DC subsets
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DOI：
10.1172/jci45416
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发表时间：
2011-05-01
影响因子：
15.9
通讯作者：
Seder, Robert A.
中科院分区：
文献类型：
--
作者：
Kastenmueller, Kathrin;Wille-Reece, Ulrike;Seder, Robert A.
非活疫苗的成功需要改进的制剂和佐剂选择，以在免疫后产生强大的T细胞免疫。在这里，使用蛋白质连接到TLR 7/8激动剂（缀合疫苗），我们研究了疫苗制剂的功能特性，细胞因子，和DC亚群需要诱导体内保护性多功能T细胞免疫。缀合物疫苗需要蛋白质的聚集以引发有效的Th 1 CD 4（+）和CD 8（+）T细胞应答。值得注意的是，缀合物疫苗，通过聚集的蛋白质和激活的TLR 7在体内，导致迁移的DC的流入LN和增加的抗原摄取的几个居民和迁移的DC子集，后者的效果强烈影响疫苗诱导的I型IFN。离体迁移性CD 8（-）DEC 205（+）CD 103（-）CD 326（-）langerin阴性真皮DCs与CD 11 c（+）CD 8（+）DCs在向初始CD 8（+）T细胞交叉提呈抗原方面同样有效。此外，这些细胞还影响Th 1 CD 4（+）T细胞的启动。总之，我们提出了一个模型，其中广泛的T细胞介导的免疫接种后的反应可以最大限度地通过共递送聚集蛋白和TLR 7/8激动剂，这一起促进最佳的抗原收购和介绍的背景下，关键的促炎细胞因子的多个DC亚群。
The success of a non-live vaccine requires improved formulation and adjuvant selection to generate robust T cell immunity following immunization. Here, using protein linked to a TLR7/8 agonist (conjugate vaccine), we investigated the functional properties of vaccine formulation, the cytokines, and the DC subsets required to induce protective multifunctional T cell immunity in vivo. The conjugate vaccine required aggregation of the protein to elicit potent Th1 CD4(+) and CD8(+) T cell responses. Remarkably, the conjugate vaccine, through aggregation of the protein and activation of TLR7 in vivo, led to an influx of migratory DCs to the LN and increased antigen uptake by several resident and migratory DC subsets, with the latter effect strongly influenced by vaccine-induced type I IFN. Ex vivo migratory CD8(-)DEC205(+)CD103(-)CD326(-) langerin-negative dermal DCs were as potent in cross-presenting antigen to naive CD8(+) T cells as CD11c(+)CD8(+) DCs. Moreover, these cells also influenced Th1 CD4(+) T cell priming. In summary, we propose a model in which broad-based T cell-mediated responses upon vaccination can be maximized by codelivery of aggregated protein and TLR7/8 agonist, which together promote optimal antigen acquisition and presentation by multiple DC subsets in the context of critical proinflammatory cytokines.