title: Mouse model for acute Epstein-Barr virus infection.
abstract: Epstein-Barr Virus (EBV) infects human B cells and drives them into continuous proliferation. Two key viral factors in this process are the latent membrane proteins LMP1 and LMP2A, which mimic constitutively activated CD40 receptor and B-cell receptor signaling, respectively. EBV-infected B cells elicit a powerful T-cell response that clears the infected B cells and leads to life-long immunity. Insufficient immune surveillance of EBV-infected B cells causes life-threatening lymphoproliferative disorders, including mostly germinal center (GC)-derived B-cell lymphomas. We have modeled acute EBV infection of naive and GC B cells in mice through timed expression of LMP1 and LMP2A. Although lethal when induced in all B cells, induction of LMP1 and LMP2A in just a small fraction of naive B cells initiated a phase of rapid B-cell expansion followed by a proliferative T-cell response, clearing the LMP-expressing B cells. Interfering with T-cell activity prevented clearance of LMP-expressing B cells. This was also true for perforin deficiency, which in the human causes a life-threatening EBV-related immunoproliferative syndrome. LMP expression in GC B cells impeded the GC reaction but, upon loss of T-cell surveillance, led to fatal B-cell expansion. Thus, timed expression of LMP1 together with LMP2A in subsets of mouse B cells allows one to study major clinically relevant features of human EBV infection in vivo, opening the way to new therapeutic approaches.
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Tristan
authors.initials: T
authors.lastname: Wirtz
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Timm
authors.initials: T
authors.lastname: Weber
authors.affiliation: Program in Cellular and Molecular Medicine, Children's Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115.|INSERM UMR 1163, Human Lymphohematopoiesis Laboratory, 75015 Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Imagine Institute,75015 Paris, France.
authors.forename: Sven
authors.initials: S
authors.lastname: Kracker
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sommermann
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; klaus.rajewsky@mdc-berlin.de tomoharu.yasuda@mdc-berlin.de.|Program in Cellular and Molecular Medicine, Children's Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.affiliation: Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany; klaus.rajewsky@mdc-berlin.de tomoharu.yasuda@mdc-berlin.de.|Program in Cellular and Molecular Medicine, Children's Hospital and Immune Disease Institute, Harvard Medical School, Boston, MA 02115.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Yasuda
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D019013:CD40 Antigens / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000821:virology; D015967:Gene Expression Regulation, Viral; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D051379:Mice; D054353:Perforin / Q000172:deficiency / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D014763:Viral Matrix Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins; D054353:Perforin
keywords: Epstein–Barr virus; LMP1; LMP2A; familial hemophagocytic lymphohistiocytosis; post-transplant lymphoproliferative disorder