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

Journal of Leukocyte Biology

Lynnsie M. Schramm¹  Kevin D. Kirschman¹  Kevin W. Tosh¹  Ronald L. Rabin  and¹  Daniela Verthelyi¹  Cecilia Tami¹  Montserrat Puig¹  Lucja T. Grajkowska¹  Joel Beren¹ 

[1] Laboratory of Immunology, Division of Therapeutic Proteins, Center for Drug Evaluation and Research,  Laboratory of Bacterial, Parasite and Allergenic Products, and Division of Veterinary Sciences, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland, USA

关键词: interferon subtypes;    CpG ODN;    imiquimod;    macaques;    skin;   

DOI  :  10.1189/jlb.0711371

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

Unknown