期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：48
页码：13821-13826
DOI：10.1073/pnas.1616574113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceEpstein-Barr Virus infects human B cells and drives them into proliferation and transformation. Although more than 90% of the human population is EBV-infected, EBV-driven pathologies including B-cell lymphomas are limited by a potent T-cell immune response. Here, we present a mouse model for acute EBV infection through conditional expression of two key EBV proteins, LMP1 and LMP2A. This model reproduces EBV-driven B-cell expansion, T-cell-mediated immune surveillance of EBV-infected B cells, and fatal lymphoproliferative disease when the T-cell response is compromised as in immunosuppressed or genetically impaired patients. It thus allows one to study EBV-host interaction functionally and from an angle that should help to develop new therapies for EBV-driven hematological diseases. 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.
