Selection of molecular structure and delivery of RNA oligonucleotides to activate TLR7 versus TLR8 and to induce high amounts of IL-12p70 in primary human monocytes
Authors
Ablasser, AndreaPoeck, Hendrik
Anz, David
Berger, Michael
Schlee, Martin
Kim, Sarah
Bourquin, Carole
Goutagny, Nadege
Jiang, Zhaozhao
Fitzgerald, Katherine A.
Rothenfusser, Simon
Endres, Stefan
Hartmann, Gunther
Hornung, Veit
UMass Chan Affiliations
Department of Medicine, Division of Infectious Diseases and ImmunologyDocument Type
Journal ArticlePublication Date
2009-05-21Keywords
Cells, CulturedDEAD-box RNA Helicases
Dendritic Cells
Humans
Interferon-alpha
Interleukin-12
Monocytes
Oligoribonucleotides
RNA
Toll-Like Receptor 7
Toll-Like Receptor 8
Immunology and Infectious Disease
Metadata
Show full item recordAbstract
Detection of non-self RNA by TLRs within endosomes and by retinoic acid-inducible gene I (RIG-I)-like helicases in the cytosol is central to mammalian antiviral immunity. In this study, we used pathway-specific agonists and targeted delivery to address RNA immunorecognition in primary human immune cells. Within PBMC, plasmacytoid dendritic cells (pDC) and monocytes were found to be responsible for IFN-alpha production upon immunorecognition of RNA. The mechanisms of RNA recognition in pDC and monocytes were distinct. In pDC, recognition of ssRNA and dsRNA oligonucleotides was TLR7-dependent, whereas a 5' triphosphate moiety (RIG-I ligand activity) had no major contribution to IFN-alpha production. In monocytes, the response to RNA oligonucleotides was mediated by either TLR8 or RIG-I. TLR8 was responsible for IL-12 induction upon endosomal delivery of ssRNA oligonucleotides and RIG-I was responsible for IFN-alpha production upon delivery of 5' triphosphate RNA into the cytosol. In conclusion, the dissection of these pathways by selecting the appropriate structure and delivery of RNA reveals pDC as major producer of IFN-alpha upon TLR-mediated stimulation and monocytes as major producer of IFN-alpha upon RIG-I-mediated stimulation. Furthermore, our results uncover the potential of monocytes to function as major producers of IL-12p70, a key Th1 cytokine classically ascribed to myeloid dendritic cells that cannot be induced by CpG oligonucleotides in the human system.Source
J Immunol. 2009 Jun 1;182(11):6824-33. Link to article on publisher's siteDOI
10.4049/jimmunol.0803001Permanent Link to this Item
http://hdl.handle.net/20.500.14038/35234PubMed ID
19454678Related Resources
Link to Article in PubMedae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.0803001