1. Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA
2. Department of Molecular, Cellular and Developmental Biology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA
3. Howard Hughes Medical Institute, and Yale University School of Medicine, New Haven, Connecticut, 06520, USA
4. These authors contributed equally to the work

Correspondence to: Ruslan Medzhitov^1,3,4Richard A. Flavell^1,3,4 Correspondence and requests for material should be addressed to R.A.F. (e-mail: Email: richard.flavell@yale.edu) or R.M. (e-mail: Email: ruslan@yale.edu). The murine TLR3 sequence has been deposited in GenBank under accession number AF420279.

Abstract

Toll-like receptors (TLRs) are a family of innate immune-recognition receptors that recognize molecular patterns associated with microbial pathogens, and induce antimicrobial immune responses^{1, 2}. Double-stranded RNA (dsRNA) is a molecular pattern associated with viral infection, because it is produced by most viruses at some point during their replication³. Here we show that mammalian TLR3 recognizes dsRNA, and that activation of the receptor induces the activation of NF-B and the production of type I interferons (IFNs). TLR3-deficient (TLR3^-/-) mice showed reduced responses to polyinosine–polycytidylic acid (poly(I:C)), resistance to the lethal effect of poly(I:C) when sensitized with d-galactosamine (d-GalN), and reduced production of inflammatory cytokines. MyD88 is an adaptor protein that is shared by all the known TLRs¹. When activated by poly(I:C), TLR3 induces cytokine production through a signalling pathway dependent on MyD88. Moreover, poly(I:C) can induce activation of NF-B and mitogen-activated protein (MAP) kinases independently of MyD88, and cause dendritic cells to mature.