title: Identification of RNA sequence motifs stimulating sequence-specific TLR8-dependent immune responses.
abstract: The TLRs 7, 8, and 9 stimulate innate immune responses upon recognizing pathogen nucleic acids. U-rich RNA sequences were recently discovered that stimulate human TLR7/8-mediated or murine TLR7-mediated immune effects. In this study we identified single-stranded RNA sequences containing defined sequence motifs that either preferentially activate human TLR8-mediated as opposed to TLR7- or TLR7/8-mediated immune responses. The identified TLR8 RNA motifs signal via TLR8 and fail to induce IFN-alpha from TLR7-expressing plasmacytoid dendritic cells but induce the secretion of Th1-like and proinflammatory cytokines from TLR8-expressing immune cells such as monocytes or myeloid dendritic cells. In contrast, RNA sequences containing the TLR7/8 motif signal via TLR7 and TLR8 and stimulate cytokine secretion from both TLR7- and TLR8-positive immunocytes. The TLR8-specific RNA sequences are able to trigger cytokine responses from human and bovine but not from mouse, rat, and porcine immune cells, suggesting that these species lack the capability to respond properly to TLR8 RNA ligands. In summary, we describe two classes of single-stranded TLR7/8 and TLR8 RNA agonists with diverse target cell and species specificities and immune response profiles.
authors.affiliation: Coley Pharmaceutical GmbH, Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Forsbach
authors.forename: Jean-Guy
authors.initials: JG
authors.lastname: Nemorin
authors.forename: Carmen
authors.initials: C
authors.lastname: Montino
authors.forename: Christian
authors.initials: C
authors.lastname: Müller
authors.forename: Ulrike
authors.initials: U
authors.lastname: Samulowitz
authors.forename: Alain P
authors.initials: AP
authors.lastname: Vicari
authors.forename: Marion
authors.initials: M
authors.lastname: Jurk
authors.forename: George K
authors.initials: GK
authors.lastname: Mutwiri
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Krieg
authors.forename: Grayson B
authors.initials: GB
authors.lastname: Lipford
authors.forename: Jörg
authors.initials: J
authors.lastname: Vollmer
mesh_terms: D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002460:Cell Line; D015226:Dinucleoside Phosphates / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009843:Oligoribonucleotides / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017423:Sequence Analysis, RNA; D013552:Swine; D051200:Toll-Like Receptor 8 / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D015226:Dinucleoside Phosphates; D016898:Interferon-alpha; D008024:Ligands; D009843:Oligoribonucleotides; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C018310:guanylyl-(3'-5')-uridine