TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.
TLR4 ligands lipopolysaccharide and monophosphoryl lipid a differentially regulate effector and memory CD8+ T Cell differentiation.
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DOI：
10.4049/jimmunol.1302569
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发表时间：
2014-05-01
期刊：
影响因子：
--
通讯作者：
Kaech SM
中科院分区：
文献类型：
--
作者：
Cui W;Joshi NS;Liu Y;Meng H;Kleinstein SH;Kaech SM
用非复制性病原体配制的疫苗需要佐剂来帮助增强免疫原性。佐剂在抗体产生中的作用已经得到了很好的研究，但它们如何影响记忆性CD 8 + T细胞分化仍然不清楚。在这里，我们实施了树突状细胞（DC）介导的免疫，研究常用的佐剂，TLR配体，对小鼠效应和记忆CD 8 + T细胞分化的影响。有趣的是，我们发现TLR 4配体LPS在免疫后产生记忆性CD 8 + T细胞方面远比其他TLR配体更上级。LPS促进克隆扩增类似于其他佐剂，但较少的活化的CD 8 + T细胞在收缩期间死亡，产生更大的记忆细胞库。令人惊讶的是，单磷酰脂质A（MPLA），另一种TLR 4配体，增强了效应CD 8 + T细胞的克隆扩增，但也促进了它们的终末分化和收缩;因此，形成的记忆CD 8 + T细胞较少，并且与LPS引发的动物相比，MPLA引发的动物对继发性感染的保护较少。此外，基因表达谱显示LPS引发的效应细胞显示出更强的促记忆基因表达特征，而MPLA引发的效应细胞的基因表达谱与末端效应CD 8 + T细胞更接近。最后，我们证明了LPS-TLR 4衍生的“促记忆”信号是MyD 88依赖性的，而不是Trif依赖性的。这项研究揭示了佐剂对CD 8 + T细胞记忆的数量和质量的影响力，并且注意佐剂的选择至关重要，因为促进效应细胞扩增可能并不总是等同于更多的记忆T细胞或更大的保护。
Vaccines formulated with non-replicating pathogens require adjuvants to help bolster immunogenicity. The role of adjuvants in antibody production has been well studied, but how they influence memory CD8+ T cell differentiation remains poorly defined. Here we implemented dendritic cell (DC)-mediated immunization to study the effects of commonly used adjuvants, TLR ligands, on effector and memory CD8+ T cell differentiation in mice. Intriguingly, we found that the TLR4 ligand LPS was far more superior to other TLR ligands in generating memory CD8+ T cells upon immunization. LPS boosted clonal expansion similar to the other adjuvants, but fewer of the activated CD8+ T cells died during contraction, generating a larger pool of memory cells. Surprisingly, monophosphoryl lipid A (MPLA), another TLR4 ligand, enhanced clonal expansion of effector CD8+ T cells, but also promoted their terminal differentiation and contraction; thus, fewer memory CD8+ T cells formed and MPLA-primed animals were less protected against secondary infection compared to those primed with LPS. Furthermore, gene expression profiling revealed that LPS-primed effector cells displayed a stronger pro-memory gene expression signature, whereas the gene expression profile of MPLA-primed effector cells aligned closer with terminal effector CD8+ T cells. Lastly, we demonstrated that the LPS-TLR4-derived “pro-memory” signals were MyD88, but not Trif, dependent. This study reveals the influential power of adjuvants on the quantity and quality of CD8+ T cell memory, and that attention to adjuvant selection is crucial because boosting effector cell expansion may not always equate with more memory T cells or greater protection.
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