Immunostimulatory RNA blocks suppression by regulatory T cells.
The role of immune suppression by regulatory T (Treg) cells in the maintenance of immune homeostasis is well established. However, little is known about how Treg cell function is inhibited on viral infection to allow the development of a protective immune response. As viral RNA is a crucial mediator for activation of antiviral immunity, we examined the effects of immunostimulatory RNA and infection with RNA viruses on Treg cell function. We show that synthetic RNA oligonucleotides potently inhibit Treg cell-induced suppression in a sequence-dependent manner. This effect is entirely dependent on TLR7 activation of APCs and subsequent IL-6 production. In addition, stimulation with the RNA viruses encephalomyocarditis virus and Sendai virus that specifically activate the RNA-sensing helicases melanoma differentiation-associated gene 5 (MDA-5) and retinoic acid-inducible gene I (RIG-I) also blocks Treg cell function. Interestingly, this effect is seen even in the absence of APCs. Consistent with this, both Treg and T effector cells express RIG-I and MDA-5. Using MDA-5-deficient mice, we demonstrate that the loss of Treg cell function on infection with encephalomyocarditis virus is strictly dependent on MDA-5 expression by Treg cells. Thus, we show in this study for the first time that activation of a RIG-I-like helicase on Treg cells blocks their suppressive function.
Anz
David
D
Division of Clinical Pharmacology, Center of Integrated Protein Science Munich, University of Munich, Munich, Germany.
Koelzer
Viktor H
VH
Moder
Stefan
S
Thaler
Raffael
R
Schwerd
Tobias
T
Lahl
Katharina
K
Sparwasser
Tim
T
Besch
Robert
R
Poeck
Hendrik
H
Hornung
Veit
V
Hartmann
Gunther
G
Rothenfusser
Simon
S
Bourquin
Carole
C
Endres
Stefan
S
D000818:Animals; D000938:Antigen-Presenting Cells; D001483:Base Sequence; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism*; D000072640:Interferon-Induced Helicase, IFIH1; D015850:Interleukin-6 / Q000096:biosynthesis; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009841:Oligonucleotides / Q000276:immunology*; D012313:RNA / Q000276:immunology*; D012328:RNA Viruses / Q000276:immunology; D012367:RNA, Viral / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D051199:Toll-Like Receptor 7 / Q000378:metabolism
D015850:Interleukin-6; D008562:Membrane Glycoproteins; D009841:Oligonucleotides; D012367:RNA, Viral; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D012313:RNA; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1