Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation
Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation
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DOI：
10.1073/pnas.1510760112
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发表时间：
2015-11-10
影响因子：
11.1
通讯作者：
Pasare, Chandrashekhar
中科院分区：
文献类型：
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作者：
Hu, Wei;Jain, Aakanksha;Pasare, Chandrashekhar
树突状细胞（DC）上的Toll样受体（TLR）识别病原体相关的分子模式导致DC成熟，这一过程涉及MHC和共刺激分子的上调以及促炎细胞因子的分泌。除了TLR 3之外的所有TLR都通过使用信号衔接子髓样分化因子88实现这些结果。TLR 4和TLR 3都可以使用含有Toll-IL-1受体结构域的衔接子诱导IFN-β（TRIF）依赖性信号传导途径，导致IFN调节因子3（IRF 3）活化和IFN-β和IFN-α 4的诱导。位于这两种TLR下游的TRIF信号通路也导致DC成熟，并且已提出I型IFN顺式作用以诱导DC成熟并随后对获得性免疫产生影响。本研究旨在了解TRIF介导的DC成熟的分子机制。我们已经发现TLR 4-TRIF诱导的DC成熟独立于IRF 3和I型IFN。相反，TLR 3介导的DC成熟完全依赖于I型IFN反馈。我们发现TLR 4-和TLR 3-TRIF轴对丝裂原活化蛋白激酶的差异活化决定了DC成熟的I型IFN依赖性。此外，我们发现LPS诱导T细胞活化的佐剂性完全独立于I型IFN。本文发现的TRIF介导的TLR 4和TLR 3信号通路之间的重要区别可能对靶向该通路的未来佐剂的设计产生重大影响。
Recognition of pathogen-associated molecular patterns by Toll-like receptors (TLRs) on dendritic cells (DCs) leads to DC maturation, a process involving up-regulation of MHC and costimulatory molecules and secretion of proinflammatory cytokines. All TLRs except TLR3 achieve these outcomes by using the signaling adaptor myeloid differentiation factor 88. TLR4 and TLR3 can both use the Toll-IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-beta and -alpha 4. The TRIF signaling pathway, downstream of both of these TLRs, also leads to DC maturation, and it has been proposed that the type I IFNs act in cis to induce DC maturation and subsequent effects on adaptive immunity. The present study was designed to understand the molecular mechanisms of TRIF-mediated DC maturation. We have discovered that TLR4-TRIF-induced DC maturation was independent of both IRF3 and type I IFNs. In contrast, TLR3-mediated DC maturation was completely dependent on type I IFN feedback. We found that differential activation of mitogen-activated protein kinases by the TLR4- and TLR3-TRIF axes determined the type I IFN dependency for DC maturation. In addition, we found that the adjuvanticity of LPS to induce T-cell activation is completely independent of type I IFNs. The important distinction between the TRIF-mediated signaling pathways of TLR4 and TLR3 discovered here could have a major impact in the design of future adjuvants that target this pathway.