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Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways

Abstract

Both lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) are adjuvants for the adaptive immune response, inducing upregulation of costimulatory molecules (UCM) on antigen-presenting cells. Trif, an adapter protein that transduces signals from Toll-like receptor 4 (TLR4) and TLR3, permits the induction of many cytokines, including interferon-β, which signals through the type I interferon receptor. We show here that LPS-induced UCM was strictly dependent on the TLR4→Trif axis, whereas dsRNA-induced UCM was only partly dependent on the TLR3→Trif axis. But both LPS- and dsRNA-induced UCM were entirely dependent on type I interferon receptor signaling. These findings show that UCM involves an autocrine or paracrine loop, and indicate that an alternative TLR3-independent, Trif-independent pathway contributes to dsRNA-induced UCM.

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Figure 1: The function of Trif and Tlr3 in UCM induced by LPS or dsRNA.
Figure 2: Cytokine production in response to LPS and dsRNA in TrifLps2/Lps2, Myd88−/− and Tlr3−/− mice.
Figure 3: The costimulatory upregulation through the TLR3 and TLR4 is regulated through different pathways.
Figure 4: Cytokine production in response to LPS and dsRNA in mice with mutations of the genes encoding Trif or IFN-RI.
Figure 5: PKR is not involved in UCM expression.
Figure 6: Phenotypic difference between strains permits genetic mapping of the dsRNA1 locus.
Figure 7: Trif and MyD88 are both required for the adjuvant effect of LPS in vivo, but only Trif is required for UCM.

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Acknowledgements

Supported by funding from the National Institutes of Health and by the Defense Advanced Research Projects Agency.

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Correspondence to Bruce Beutler.

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Hoebe, K., Janssen, E., Kim, S. et al. Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways. Nat Immunol 4, 1223–1229 (2003). https://doi.org/10.1038/ni1010

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