TLR9 and TLR7 agonists mediate distinct type I IFN responses in humans and nonhuman primates in vitro and in vivo

Human I-IFNs include IFN- and 13 independently regulated subtypes of IFN- (I-IFNs). TLR7 and -9 induce IIFNs, 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-1/ 13, -2, and -14. In contrast, TLR9 agonists, regardless of the type used (CpG C-, B-, or D-ODN), prompted slower but sustained expression of IFN-1/13, -2, -7, -8, -10, -14, -16, and -21. 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-8, 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- 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. J. Leukoc. Biol. 91: 147–158; 2012.