B7-H1, which represses EBV-immortalized B cell killing by autologous T and NK cells, is oppositely regulated by c-Myc and EBV latency III program at both mRNA and secretory lysosome levels.
EBV-immortalized B cells induce a complex immune response such that the virus persists as a clinically silent infection for the lifetime of the infected host. B7-H1, also called PD-L1, is a cosignaling molecule of the B7 family that can inhibit activated T cell effectors by interaction with its receptor PD-1. In this work, we have studied the dependence of B7-H1 on NF-κB and c-Myc, the two main transcription factors in EBV latency III proliferating B cells, on various lymphoblastoid and Burkitt lymphoma cell lines, some of them being inducible or not for the EBV latency III program and/or for c-Myc. We found that B7-H1 repressed killing of EBV-immortalized B cells by their autologous T and NK cells. At the mRNA level, NF-κB was a weak inducer whereas c-Myc was a strong repressor of B7-H1 expression, an effect mediated by STAT1 inhibition. At the protein level, B7-H1 molecules were stored in both degradative and unconventional secretory lysosomes. Surface membrane B7-H1 molecules were constitutively internalized and proteolyzed in lysosomes. The EBV latency III program increased the amounts of B7-H1-containing secretory lysosomes and their export to the surface membrane. By repressing actin polymerization, c-Myc blocked secretory lysosome migration and B7-H1 surface membrane export. In addition to B7-H1, various immunoregulatory molecules participating in the immunological synapse are stored in secretory lysosomes. By playing on actin polymerization, c-Myc could thus globally regulate the immunogenicity of transformed B cells, acting on export of secretory lysosomes to plasma membrane.
Centre National de la Recherche Scientifique, Unité Mixte de Recherche CNRS 7276, Faculté de Médecine, 87025 Limoges Cedex, France.
Stéphanie
S
Durand-Panteix
Mona
M
Farhat
Ibtissam
I
Youlyouz-Marfak
Pauline
P
Rouaud
Catherine
C
Ouk-Martin
Amandine
A
David
Nathalie
N
Faumont
Jean
J
Feuillard
Chantal
C
Jayat-Vignoles
D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D001693:Biological Transport, Active / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D012367:RNA, Viral / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D017735:Virus Latency / Q000276:immunology*
D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D012367:RNA, Viral