title: TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo.
abstract: Human I-IFNs include IFN-β and 13 independently regulated subtypes of IFN-α (I-IFNs). TLR7 and -9 induce I-IFNs, but it is unknown whether their subtype repertoire is similar. This study used new PCR arrays that selectively amplify individual I-IFN subtype genes of human and nonhuman primates to characterize the TLR7- and -9-mediated IFN response in vitro and in vivo. We show that in human PBMCs, TLR7 agonists induce a rapid burst of I-IFN transcripts, consisting primarily of IFN-α1/13, -α2, and -α14. In contrast, TLR9 agonists, regardless of the type used (CpG C-, B-, or D-ODN), prompted slower but sustained expression of IFN-α1/13, -α2, -α7, -α8, -α10, -α14, -α16, and -α21. These qualitative differences were translated downstream as differences in the pattern of IFN-inducible genes. In macaque PBMCs, imiquimod produced a short burst of IFN mRNA, dominated by IFN-α8, whereas C- or D-ODN induced a greater than tenfold increase in transcripts for all I-IFN subtypes by 12 h of culture. Differences were more evident in vivo, where TLR7 and -9 agonists induced significantly different levels of I-IFN transcripts in skin. Although the rates of gene transcription differed significantly for individual TLR9 agonists, their IFN-α subtype signature was almost identical, indicating that the type of receptor dictates the quality of the I-IFN response in vitro and in vivo. These results may underlie the differential therapeutic effects of TLR7 and -9 agonists and should inform future clinical studies.
authors: Laboratory of Immunology, Division of Therapeutic Proteins, Center for Drug Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA.
authors: Montserrat
authors: M
authors: Puig
authors: Kevin W
authors: KW
authors: Tosh
authors: Lynnsie M
authors: LM
authors: Schramm
authors: Lucja T
authors: LT
authors: Grajkowska
authors: Kevin D
authors: KD
authors: Kirschman
authors: Cecilia
authors: C
authors: Tami
authors: Joel
authors: J
authors: Beren
authors: Ronald L
authors: RL
authors: Rabin
authors: Daniela
authors: D
authors: Verthelyi
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D000077271:Imiquimod; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D008253:Macaca mulatta; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics; D051217:Toll-Like Receptor 9 / Q000819:agonists* / Q000235:genetics
chemical_list: D000634:Aminoquinolines; D007370:Interferon Type I; C495348:TLR7 protein, human; C495371:TLR9 protein, human; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D000077271:Imiquimod