Influenza A virus elevates active cathepsin B in primary murine DC.
Dendritic cells (DCs) act as a first-line recognition system for invading pathogens, such as influenza A. The interaction of DC with influenza A virus results in DC activation via endosomal Toll-like receptors and also leads to presentation of viral peptides on MHC class II molecules. Prior work demonstrated that influenza A virus (A/HKx31; H3N2) infection of BALB/c mice activates lung DCs for antigen presentation, and that the enhanced function of these cells persists long after viral clearance and resolution of the virus-induced inflammatory response. Whether influenza A virus has acute or longer-lasting effects on the endo/lysosomal antigen-processing machinery of DCs has not been studied. Here, we show that antigen presentation from intact protein antigen, but not peptide presentation, results in increased T cell stimulation by influenza-exposed lung DCs, suggesting increased antigen processing/loading in these DCs. We find that cathepsin (Cat) B levels and activity are substantially up-regulated in murine lung DCs, harvested 30 days after A/HKx31 infection. CatB levels and activity are also increased in murine splenic and bone marrow-derived DCs, following short-term in vitro exposure to UV-inactivated influenza A virus. Modest effects on CatX are also seen during in vivo and in vitro exposure to influenza A virus. Using a cell permeable Cat inhibitor, we show Cats in influenza-exposed DCs to be functional and required for generation of a T cell epitope from intact ovalbumin. Our findings indicate that influenza A virus affects the MHC class II antigen-processing pathway, an essential pathway for CD4(+) T cell activation.
Burster
Timo
T
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
Giffon
Thierry
T
Dahl
Martin E
ME
Björck
Pia
P
Bogyo
Matthew
M
Weber
Ekkehard
E
Mahmood
Kutubuddin
K
Lewis
David B
DB
Mellins
Elizabeth D
ED
D000818:Animals; D017951:Antigen Presentation; D001854:Bone Marrow Cells / Q000166:cytology*; D002401:Cathepsin B / Q000096:biosynthesis / Q000378:metabolism*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D009980:Influenza A virus / Q000276:immunology* / Q000528:radiation effects; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D013154:Spleen / Q000166:cytology
D002401:Cathepsin B