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

Abstract

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.

Reversion of apoptotic resistance of TP53-mutated Burkitt lymphoma B-cells to spindle poisons by exogenous activation of JNK and p38 MAP kinases

“…58 For western blots, primary antibodies were anti PARP (Rabbit polyclonal 9542, Cell signaling, at 1/1000), anti caspase 3 (Rabbit mAb 8G10, Cell signaling, St-Qentin-en-Yvelines, France at 1/1000), anti-cleaved caspase 3 (Rabbit polyclonal D175, Cell signaling, at 1/1000) and anti α -tubulin (sc-23948, Santa Cruz at 1/200). Secondary horseradish peroxidase-conjugated goat anti-mouse or anti-rabbit immunoglobulins (Bio-Rad, Marnes-la-Coquette, France) were used at 1/5000 for 1 h.…”

The role of EBV in the pathogenesis of Burkitt’s Lymphoma: an Italian hospital based survey

“…The main viral genes involved in the transformation and persistence of infected B cells are LMP1 and LMP2a. Through self-aggregation on the surface of the infected B cell, LMP1 and LMP2a provide active signals leading to the proliferation of transformed memory B cells that remain in the host for life [1]. LMP1 and other EBV proteins such as Epstein Barr Nuclear Antigen 2 (EBNA2), are highly antigenic, marking the infected B cells for destruction by cytotoxic T cells (CTLs) in the healthy individual.…”

“…LMP1 and other EBV proteins such as Epstein Barr Nuclear Antigen 2 (EBNA2), are highly antigenic, marking the infected B cells for destruction by cytotoxic T cells (CTLs) in the healthy individual. On the other hand, in immunodepressed patients as well as in transplant recipients undergoing immunosuppression, CTLs are immobilized, allowing for the proliferation and immortalization of infected B cells [1]. EBV has been demonstrated to be involved in the development of numerous malignancies, both in immunocompetent hosts and in immunocompromised individuals [2].…”

Burkitt’s Lymphoma Presenting as Late-Onset Posttransplant Lymphoproliferative Disorder following Kidney and Pancreas Transplantation: Case Report and Review of the Literature

“…The main viral genes involved in the transformation and persistence of infected B cells are LMP1 and LMP2a. Through self-aggregation on the surface of the infected B cell, LMP2a and LMP1 provide tonic signals leading to the proliferation of transformed memory B cells that remain in the host for life [3]. LMP1 and other EBV proteins such as EBNA 2, are highly antigenic, marking the infected B cells for destruction by cytotoxic T cells (CTLs) in the healthy individual.…”

“…LMP1 and other EBV proteins such as EBNA 2, are highly antigenic, marking the infected B cells for destruction by cytotoxic T cells (CTLs) in the healthy individual. However, in transplant recipients undergoing immunosuppression, CTLs are immobilized, allowing for the proliferation and immortalization of infected B cells [3]. Posttransplant immunosuppression in HCST recipients typically lasts for 6 months.…”