International Immunology Advance Access originally published online on April 19, 2007
International Immunology 2007 19(5):645-655; doi:10.1093/intimm/dxm030
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Influenza A virus elevates active cathepsin B in primary murine DC
1 Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
2 Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
3 Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA
4 Institute of Physiological Chemistry, Martin Luther University Halle-Wittenberg, Halle, Germany
5 MedImmune Vaccines, Mountain View, CA 94043, USA
6 Present address: Roche Palo Alto LLC, Palo Alto, CA 94304, USA
7 Present address: Novavax, Inc. Malvern, PA 19355, USA
Correspondence to: T. Burster; E-mail: tburster{at}stanford.edu or E. Mellins; E-mail: mellins{at}stanford.edu
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.
Keywords: Cathepsin B, dendritic cells, influenza A
Transmitting editor: R. Medzhitov
Received 29 July 2006, accepted 23 February 2007.