Research ArticleImmunology

Type I interferon signaling contributes to the bias that Toll-like receptor 4 exhibits for signaling mediated by the adaptor protein TRIF

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Science Signaling  11 Nov 2014:
Vol. 7, Issue 351, pp. ra108
DOI: 10.1126/scisignal.2005442

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Toward Better Vaccine Adjuvants

The increasing use of vaccines based on components of pathogens rather than on whole pathogens requires the development of vaccine adjuvants to boost immune responses. Toll-like receptor 4 (TLR4) is a pattern-recognition receptor that stimulates immune signaling pathways through two adaptor proteins: MyD88 and TRIF. Whereas MyD88-dependent signaling leads to potentially harmful inflammatory responses, TRIF-dependent signaling leads to immunostimulatory responses. Current adjuvant strategies are based on the idea that the structures of TLR4 agonists determine which adaptor protein the receptor uses. However, Kolb et al. found that TLR4 signaling is inherently biased toward the TRIF-dependent pathway. TRIF-dependent bias of a vaccine adjuvant occurred with concentrations sufficient for TRIF, but limiting for MyD88, signaling. Without type I interferon signaling, TLR4 required higher concentrations of agonist, thereby equivalently stimulating both TRIF- and MyD88-dependent pathways. These data may aid in the development of more effective vaccine adjuvants that enhance the immune response without triggering undesirable inflammatory reactions.

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