Two mechanistically distinct immune evasion proteins of cowpox virus combine to avoid antiviral CD8 T cells.
Downregulation of MHC class I on the cell surface is an immune evasion mechanism shared by many DNA viruses, including cowpox virus. Previously, a cowpox virus protein, CPXV203, was shown to downregulate MHC class I. Here we report that CPXV12 is the only other MHC class I-regulating protein of cowpox virus and that it uses a mechanism distinct from that of CPXV203. Whereas CPXV203 retains fully assembled MHC class I by exploiting the KDEL-mediated endoplasmic reticulum retention pathway, CPXV12 binds to the peptide-loading complex and inhibits peptide loading on MHC class I molecules. Viruses deleted of both CPXV12 and CPXV203 demonstrated attenuated virulence in a CD8 T cell-dependent manner. These data demonstrate that CPXV12 and CPXV203 proteins combine to ablate MHC class I expression and abrogate antiviral CD8 T cell responses.
Byun
Minji
M
Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Verweij
Marieke C
MC
Pickup
David J
DJ
Wiertz
Emmanuel J H J
EJ
Hansen
Ted H
TH
Yokoyama
Wayne M
WM
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015605:Cowpox / Q000276:immunology*; D015608:Cowpox virus / Q000472:pathogenicity / Q000502:physiology*; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D057131:Immune Evasion; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D002352:Carrier Proteins; D015395:Histocompatibility Antigens Class I; D014764:Viral Proteins