Endocytosed soluble cowpox virus protein CPXV 012 inhibits antigen cross‐presentation in human monocyte‐derived dendritic cells

Abstract Viruses may interfere with the MHC class I antigen presentation pathway in order to avoid CD 8 + T cell‐mediated immunity. A key target within this pathway is the peptide transporter TAP . This transporter plays a central role in MHC class I‐mediated peptide presentation of endogenous antigens. In addition, TAP plays a role in antigen cross‐presentation of exogenously derived antigens by dendritic cells ( DC s). In this study, a soluble form of the cowpox virus TAP inhibitor CPXV 012 is synthesized for exogenous delivery into the antigen cross‐presentation route of human monocyte‐derived (mo) DC s. We show that soluble CPXV 012 localizes to TAP + compartments that carry internalized antigen and is a potent inhibitor of antigen cross‐presentation. CPXV 012 stimulates the prolonged deposition of antigen fragments in storage compartments of mo DC s, as a result of reduced endosomal acidification and reduced antigen proteolysis when soluble CPXV 012 is present. Thus, a dual function can be proposed for CPXV 012: inhibition of TAP ‐mediated peptide transport and inhibition of endosomal antigen degradation. We propose this second function for soluble CPXV 012 can serve to interfere with antigen cross‐presentation in a peptide transport‐independent manner.