Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling

Yue Guan, Diana Rose E. Ranoa, Song Jiang, Sarita K. Mutha, Xinyan Li, Jerome Baudry, Richard I. Tapping

    Research output: Contribution to journalArticlepeer-review

    Abstract

    TLRs are central receptors of the innate immune system that drive host inflammation and adaptive immune responses in response to invading microbes. Among human TLRs, TLR10 is the only family member without a defined agonist or function. Phylogenetic analysis reveals that TLR10 is most related to TLR1 and TLR6, both of which mediate immune responses to a variety of microbial and fungal components in cooperation with TLR2. The generation and analysis of chimeric receptors containing the extracellular recognition domain of TLR10 and the intracellular signaling domain of TLR1, revealed that TLR10 senses triacylated lipopeptides and a wide variety of other microbial-derived agonists shared by TLR1, but not TLR6. TLR10 requires TLR2 for innate immune recognition, and these receptors colocalize in the phagosome and physically interact in an agonist-dependent fashion. Computational modeling and mutational analysis of TLR10 showed preservation of the essential TLR2 dimer interface and lipopeptide-binding channel found in TLR1. Coimmunoprecipitation experiments indicate that, similar to TLR2/1, TLR2/10 complexes recruit the proximal adaptor MyD88 to the activated receptor complex. However, TLR10, alone or in cooperation with TLR2, fails to activate typical TLR-induced signaling, including NF-κB-, IL-8-, or IFN-β-driven reporters. We conclude that human TLR10 cooperates with TLR2 in the sensing of microbes and fungi but possesses a signaling function distinct from that of other TLR2 subfamily members.

    Original languageEnglish (US)
    Pages (from-to)5094-5103
    Number of pages10
    JournalJournal of Immunology
    Volume184
    Issue number9
    DOIs
    StatePublished - May 1 2010

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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