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The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors

Nature volume 420, pages 329–333 (2002)Cite this article

Abstract

Mammalian Toll-like receptors (TLRs) function as sensors of infection and induce the activation of innate and adaptive immune responses1,2,3. Upon recognizing conserved pathogen-associated molecular products, TLRs activate host defence responses through their intracellular signalling domain, the Toll/interleukin-1 receptor (TIR) domain, and the downstream adaptor protein MyD88 (refs 1–3). Although members of the TLR and the interleukin-1 (IL-1) receptor families all signal through MyD88, the signalling pathways induced by individual receptors differ. TIRAP, an adaptor protein in the TLR signalling pathway, has been identified and shown to function downstream of TLR4 (refs 4, 5). Here we report the generation of mice deficient in the Tirap gene. TIRAP-deficient mice respond normally to the TLR5, TLR7 and TLR9 ligands, as well as to IL-1 and IL-18, but have defects in cytokine production and in activation of the nuclear factor NF-κB and mitogen-activated protein kinases in response to lipopolysaccharide, a ligand for TLR4. In addition, TIRAP-deficient mice are also impaired in their responses to ligands for TLR2, TLR1 and TLR6. Thus, TIRAP is differentially involved in signalling by members of the TLR family and may account for specificity in the downstream signalling of individual TLRs.

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Figure 1: Generation of TIRAP-deficient mice.
Figure 2: Impaired proliferation of TIRAP-deficient splenocytes to LPS and BLP but not CpG and R-848.
Figure 3: TIRAP-deficient DCs are significantly impaired in LPS- and BLP-induced cytokine production.
Figure 4: TIRAP is not involved in IL-1 and IL-18 signalling.
Figure 5: TIRAP-deficient macrophages activate NF-κB and MAP kinases with delayed kinetics in response to LPS and BLP but not CpG.

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Acknowledgements

We thank S. Akira for the MyD88-deficient mice; L. Kopp and C. Pasare for discussion and reading the manuscript; C. Annicelli for maintaining the mouse colony; L. Evangeliate for technical assistance; L. Alexopoulou and K. Kobayashi for technical advice; and the Yale Cancer Center Transgenic Mouse and Gene Targeting Resource for blastocyst injections. This work was supported by the NIH, the Searle Foundation (R.M.) and the Howard Hughes Medical Institute (R.M., T.H., G.B. and R.F.).

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  1. Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, Connecticut, 06520, New Haven, USA

    Tiffany Horng, Gregory M. Barton, Richard A. Flavell & Ruslan Medzhitov

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  1. Tiffany Horng
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Correspondence to Ruslan Medzhitov.

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Horng, T., Barton, G., Flavell, R. et al. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature 420, 329–333 (2002). https://doi.org/10.1038/nature01180

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