Asparagine endopeptidase controls anti-influenza virus immune responses through TLR7 activation.
Intracellular Toll-like receptors (TLRs) expressed by dendritic cells recognize nucleic acids derived from pathogens and play an important role in the immune responses against the influenza virus (IAV), a single-stranded RNA sensed by different receptors including TLR7. However, the importance of TLR7 processing in the development of anti-viral immune responses is not known. Here we report that asparagine endopeptidase (AEP) deficient mice are unable to generate a strong anti-IAV response, as demonstrated by reduced inflammation, cross presentation of cell-associated antigens and priming of CD8(+) T cells following TLR7-dependent pulmonary infection induced by IAV. Moreover, AEP deficient lung epithelial- or myeloid-cells exhibit impaired TLR7 signaling due to defective processing of this receptor. Indeed, TLR7 requires a proteolytic cleavage by AEP to generate a C-terminal fragment competent for signaling. Thus, AEP activity is critical for TLR7 processing, opening new possibilities for the treatment of influenza and TLR7-dependent inflammatory diseases.
INSERM, Unité 1013, Paris, France.
Sophia
S
Maschalidi
Signe
S
Hässler
Fany
F
Blanc
Fernando E
FE
Sepulveda
Mira
M
Tohme
Michel
M
Chignard
Peter
P
van Endert
Mustapha
M
Si-Tahar
Delphyne
D
Descamps
Bénédicte
B
Manoury
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D010450:Endopeptidases