title: Latent Membrane Protein LMP2A Impairs Recognition of EBV-Infected Cells by CD8+ T Cells.
abstract: The common pathogen Epstein-Barr virus (EBV) transforms normal human B cells and can cause cancer. Latent membrane protein 2A (LMP2A) of EBV supports activation and proliferation of infected B cells and is expressed in many types of EBV-associated cancer. It is not clear how latent EBV infection and cancer escape elimination by host immunity, and it is unknown whether LMP2A can influence the interaction of EBV-infected cells with the immune system. We infected primary B cells with EBV deleted for LMP2A, and established lymphoblastoid cell lines (LCLs). We found that CD8+ T cell clones showed higher reactivity against LMP2A-deficient LCLs compared to LCLs infected with complete EBV. We identified several potential mediators of this immunomodulatory effect. In the absence of LMP2A, expression of some EBV latent antigens was elevated, and cell surface expression of MHC class I was marginally increased. LMP2A-deficient LCLs produced lower amounts of IL-10, although this did not directly affect CD8+ T cell recognition. Deletion of LMP2A led to several changes in the cell surface immunophenotype of LCLs. Specifically, the agonistic NKG2D ligands MICA and ULBP4 were increased. Blocking experiments showed that NKG2D activation contributed to LCL recognition by CD8+ T cell clones. Our results demonstrate that LMP2A reduces the reactivity of CD8+ T cells against EBV-infected cells, and we identify several relevant mechanisms.
authors.affiliation: Clinical Cooperation Group Immunooncology, Department of Medicine III, Klinikum der Universität München, and Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research (DZIF), Munich, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rancan
authors.affiliation: Clinical Cooperation Group Immunooncology, Department of Medicine III, Klinikum der Universität München, and Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Leah
authors.initials: L
authors.lastname: Schirrmann
authors.affiliation: Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Hüls
authors.affiliation: Clinical Cooperation Group Immunooncology, Department of Medicine III, Klinikum der Universität München, and Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research (DZIF), Munich, Germany; Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany; Department of Otorhinolaryngology, Klinikum der Universität München, Munich, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Zeidler
authors.affiliation: Clinical Cooperation Group Immunooncology, Department of Medicine III, Klinikum der Universität München, and Research Unit Gene Vectors, Helmholtz Zentrum München, Munich, Germany; German Center for Infection Research (DZIF), Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Moosmann
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000276:immunology*; D019309:Epstein-Barr Virus Nuclear Antigens / Q000276:immunology*; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000276:immunology; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection; D014763:Viral Matrix Proteins / Q000276:immunology*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D014763:Viral Matrix Proteins