The Epstein-Barr virus-encoded BILF1 protein modulates immune recognition of endogenously processed antigen by targeting major histocompatibility complex class I molecules trafficking on both the exocytic and endocytic pathways.
Despite triggering strong immune responses, Epstein-Barr virus (EBV) has colonized more than 90% of the adult human population. Successful persistence of EBV depends on the establishment of a balance between host immune responses and viral immune evasion. Here we have extended our studies on the EBV-encoded BILF1 protein, which was recently identified as an immunoevasin that functions by enhancing degradation of major histocompatibility complex class I (MHC-I) antigens via lysosomes. We now demonstrate that disruption of the EKT signaling motif of BILF1 by a K122A mutation impairs the ability of BILF1 to enhance endocytosis of surface MHC-I molecules, while subsequent lysosomal degradation was impaired by deletion of the 21-residue C-terminal tail of BILF1. Furthermore, we identified another mechanism of BILF1 immunomodulation: it targets newly synthesized MHC-I/peptide complexes en route to the cell surface. Importantly, although the diversion of MHC-I on the exocytic pathway caused a relatively modest reduction in cell surface MHC-I, presentation of endogenously processed target peptides to immune CD8(+) effector T cells was reduced by around 65%. The immune-modulating functions of BILF1 in the context of the whole virus were confirmed in cells lytically infected with a recombinant EBV in which BILF1 was deleted. This study therefore extends our initial observations on BILF1 to show that this immunoevasin can target MHC-I antigen presentation via both the exocytic and endocytic trafficking pathways. The results also emphasize the merits of including functional T cell recognition assays to gain a more complete picture of immunoevasin effects on the antigen presentation pathway.
Cancer Research UK Birmingham Cancer Centre, University of Birmingham, Birmingham, United Kingdom.
Jianmin
J
Zuo
Laura L
LL
Quinn
Jennifer
J
Tamblyn
Wendy A
WA
Thomas
Regina
R
Feederle
Henri-Jacques
HJ
Delecluse
Andrew D
AD
Hislop
Martin
M
Rowe
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D002460:Cell Line; D004705:Endocytosis / Q000276:immunology*; D005089:Exocytosis / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000472:pathogenicity* / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014764:Viral Proteins / Q000378:metabolism*
C495131:BILF1 protein, Epstein-Barr virus; D015395:Histocompatibility Antigens Class I; D043562:Receptors, G-Protein-Coupled; D014764:Viral Proteins