TLR8-driven IL-12-dependent reciprocal and synergistic activation of NK cells and monocytes by immunostimulatory RNA.
Immunostimulatory RNA (isRNA) depending on sequence and structure can function as a ligand for Toll-like receptor (TLR) 7 and TLR8. Here we show that isRNA induces high levels of bioactive interleukin-12 in purified human monocytes, whereas purified natural killer (NK) cells did not respond. However, in a coculture of monocytes and NK cells, isRNA dramatically increased NK cell function. Activation of monocytes and NK cells was bidirectional, as monocytes in the presence of NK cells produced higher levels of bioactive interleukin-12. As a result of the monocyte-NK cell interaction in peripheral blood mononuclear cells isRNA induced high levels of interferon (IFN)-gamma in NK cells and strong NK cell-mediated cytotoxic activity. Induction of simultaneous IFN-gamma production and lytic activity by isRNA in NK cells was higher as compared with other established nucleic acid or small molecule TLR ligands. Our studies demonstrate that monocytes play a pivotal role in the orchestration of a strong NK cell response. With early NK cell-dependent IFN-gamma production being critical for the development of antigen-specific cytotoxic T lymphocyte responses, newly developed isRNA-based TLR8 ligands join the list of promising oligonucleotides for immunotherapy of viral infection and cancer.
Berger
Michael
M
Division of Clinical Pharmacology, Department of Internal Medicine, Ludwig-Maximilians University of Munich, Germany.
Ablasser
Andrea
A
Kim
Sarah
S
Bekeredjian-Ding
Isabelle
I
Giese
Thomas
T
Endres
Stefan
S
Hornung
Veit
V
Hartmann
Gunther
G
D000818:Animals; D002450:Cell Communication / Q000276:immunology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D012313:RNA / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D051200:Toll-Like Receptor 8 / Q000819:agonists / Q000276:immunology*
D008024:Ligands; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D018664:Interleukin-12; D012313:RNA; D007371:Interferon-gamma