title: Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition.
abstract: Cowpox virus encodes an extensive array of putative immunomodulatory proteins, likely contributing to its wide host range, which includes zoonotic infections in humans. Unlike Vaccinia virus, cowpox virus prevents stimulation of CD8(+) T cells, a block that correlated with retention of MHC class I in the endoplasmic reticulum by the cowpox virus protein CPXV203. However, deletion of CPXV203 did not restore MHC class I transport or T cell stimulation. Here, we demonstrate the contribution of an additional viral protein, CPXV12, which interferes with MHC class I/peptide complex formation by inhibiting peptide translocation by the transporter associated with antigen processing (TAP). Importantly, human and mouse MHC class I transport and T cell stimulation was restored upon deletion of both CPXV12 and CPXV203, suggesting that these unrelated proteins independently mediate T cell evasion in multiple hosts. CPXV12 is a truncated version of a putative NK cell ligand, indicating that poxviral gene fragments can encode new, unexpected functions.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006, USA.
authors.forename: Dina
authors.initials: D
authors.lastname: Alzhanova
authors.forename: David M
authors.initials: DM
authors.lastname: Edwards
authors.forename: Erika
authors.initials: E
authors.lastname: Hammarlund
authors.forename: Isabel G
authors.initials: IG
authors.lastname: Scholz
authors.forename: Daniëlle
authors.initials: D
authors.lastname: Horst
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Wagner
authors.forename: Chris
authors.initials: C
authors.lastname: Upton
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Wiertz
authors.forename: Mark K
authors.initials: MK
authors.lastname: Slifka
authors.forename: Klaus
authors.initials: K
authors.lastname: Früh
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017951:Antigen Presentation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D015605:Cowpox / Q000276:immunology*; D015608:Cowpox virus / Q000472:pathogenicity / Q000502:physiology*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D057131:Immune Evasion; D051379:Mice; D011485:Protein Binding; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014779:Virus Replication
chemical_list: D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins; C477327:transporter associated with antigen processing (TAP)