The TLR7 agonist R848 alleviates allergic inflammation by targeting invariant NKT cells to produce IFN-gamma.
It has been documented that TLR7 stimulation triggers not only antiviral responses, but also alleviates experimental asthma. Considering the implication of invariant NKT (iNKT) cells in both situations, we postulated that they might contribute to the anti-inflammatory effect of TLR7 ligands. We show in this study that spleen cells activated by the TLR7 agonist resiquimod (R848) attenuate allergic inflammation upon adoptive transfer when they are recovered from wild-type, but not from iNKT cell-deficient Jα18(-/-) mice, which proves the specific involvement of this regulatory population. Furthermore, we provide evidence that IFN-γ is critical for the protective effect, which is lost when transferred iNKT cells are sorted from IFN-γ-deficient mice. In support of a direct activation of iNKT cells through TLR7 signaling in vivo, we observed a prompt increase of serum IFN-γ levels, associated with upregulation of CD69 expression on iNKT cells. Moreover, we demonstrate that iNKT cells effectively express TLR7 and respond to R848 in vitro by producing high levels of IFN-γ in the presence of IL-12, consistent with the conclusion that their contribution to the alleviation of allergic inflammation upon treatment with TLR7 ligands is mediated through IFN-γ.
Université Paris Descartes, Faculté de Médecine-Centre National de la Recherche Scientifique Unité Mixte de Recherche 8147, Hôpital Necker, Paris, France.
Françoise
F
Grela
Aude
A
Aumeunier
Emilie
E
Bardel
Linh Pham
LP
Van
Elvire
E
Bourgeois
Jeroen
J
Vanoirbeek
Maria
M
Leite-de-Moraes
Elke
E
Schneider
Michel
M
Dy
André
A
Herbelin
Nathalie
N
Thieblemont
D019264:Adoptive Transfer; D000818:Animals; D018926:Anti-Allergic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D016503:Drug Delivery Systems / Q000379:methods*; D007093:Imidazoles / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000096:biosynthesis*; D008562:Membrane Glycoproteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*
D018926:Anti-Allergic Agents; D007093:Imidazoles; D018836:Inflammation Mediators; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D007371:Interferon-gamma; D010047:Ovalbumin; C402365:resiquimod