Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice
Using 3 TLR ligands as a combination adjuvant induces qualitative changes in T cell responses needed for antiviral protection in mice
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DOI：
10.1172/jci39293
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发表时间：
2010-02-01
影响因子：
15.9
通讯作者：
Berzofsky, Jay A.
中科院分区：
文献类型：
--
作者：
Zhu, Qing;Egelston, Colt;Berzofsky, Jay A.
TLR配体是开发新型疫苗佐剂的有希望的候选者，可以引发针对新发传染病的保护性免疫。佐剂最常用于增加免疫应答的数量。然而，T细胞反应的质量可能比数量更重要。刺激某些tlr对可诱导协同反应，激活树突状细胞并通过克隆扩增诱导/增强T细胞反应，从而增加应答T细胞的数量。在这里，我们发现，与仅使用其中任意2种tlr的配体相比，使用3种tlr （TLR2/6、TLR3和TLR9）的配体大大提高了用HIV包膜肽接种小鼠的保护效果；令人惊讶的是，增强的保护作用并没有显著增加肽特异性T细胞的数量。相反，这3种TLR配体的组合主要通过增强它们对抗原的功能亲和力来增强T细胞应答的质量，这是清除病毒所必需的。三重组合增加了DC IL-15及其受体IL-15R α的产生，这有助于高亲和力，减少程序性死亡配体1的表达和诱导Tregs。因此，选择性TLR配体组合可以通过提高T细胞反应的质量而不是数量来提高保护效果。
TLR ligands are promising candidates for the development of novel vaccine adjuvants that can elicit protective immunity against emerging infectious diseases. Adjuvants have been used most frequently to increase the quantity of an immune response. However, the quality of a T cell response can be more important than its quantity. Stimulating certain pairs of TLRs induces a synergistic response in terms of activating dendritic cells and eliciting/enhancing T cell responses through clonal expansion, which increases the number of responding T cells. Here, we have found that utilizing figands for 3 TLRs (TLR2/6, TLR3, and TLR9) greatly increased the protective efficacy of vaccination with an HIV envelope peptide in mice when compared with using ligands for only any 2 of these TLRs; surprisingly, increased protection was induced without a marked increase in the number of peptide-specific T cells. Rather, the combination of these 3 TLR ligands augmented the quality of the T cell responses primarily by amplifying their functional avidity for the antigen, which was necessary for clearance of virus. The triple combination increased production of DC IL-15 along with its receptor, IL-15R alpha, which contributed to high avidity, and decreased expression of programmed death-ligand 1 and induction of Tregs. Therefore, selective TLR ligand combinations can increase protective efficacy by increasing the quality rather than the quantity of T cell responses.