Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation

Wei Hu, Aakanksha Jain, Yajing Gao, Igor M. Dozmorov, Rajakumar Mandraju, Edward K. Wakeland, Chandrashekhar Pasare

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26 Citations (Scopus)

Abstract

Recognition of pathogen-Associated molecular patterns by Tolllike 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-β (TRIF)-dependent signaling pathway leading to IFN regulatory factor 3 (IRF3) activation and induction of IFN-β and-α4. 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.

Original languageEnglish (US)
Pages (from-to)13994-13999
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number45
DOIs
StatePublished - Nov 10 2015

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Dendritic Cells
Interferon Regulatory Factor-3
Myeloid Differentiation Factor 88
Toll-Like Receptor 3
Interleukin-1 Receptors
Adaptive Immunity
Mitogen-Activated Protein Kinases
Up-Regulation
Cytokines
T-Lymphocytes

ASJC Scopus subject areas

  • General

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Differential outcome of TRIF-mediated signaling in TLR4 and TLR3 induced DC maturation. / Hu, Wei; Jain, Aakanksha; Gao, Yajing; Dozmorov, Igor M.; Mandraju, Rajakumar; Wakeland, Edward K.; Pasare, Chandrashekhar.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 45, 10.11.2015, p. 13994-13999.

Research output: Contribution to journalArticle

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