Immune Surveillance and Therapy of Lymphomas Driven by Epstein-Barr Virus Protein LMP1 in a Mouse Model
Menée sur un modèle murin immunodéprimé, cette étude met en évidence le rôle joué par la protéine LMP1 dans la surveillance immunitaire et la transformation de cellules B infectées par le virus d'Epstein-Barr
B cells infected by Epstein-Barr virus (EBV), a transforming virus endemic in humans, are rapidly cleared by the immune system, but some cells harboring the virus persist for life. Under conditions of immunosuppression, EBV can spread from these cells and cause life-threatening pathologies. We have generated mice expressing the transforming EBV latent membrane protein 1 (LMP1), mimicking a constitutively active CD40 coreceptor, specifically in B cells. Like human EBV-infected cells, LMP1+ B cells were efficiently eliminated by T cells, and breaking immune surveillance resulted in rapid, fatal lymphoproliferation and lymphomagenesis. The lymphoma cells expressed ligands for a natural killer (NK) cell receptor, NKG2D, and could be targeted by an NKG2D-Fc fusion protein. These experiments indicate a central role for LMP1 in the surveillance and transformation of EBV-infected B cells in vivo, establish a preclinical model for B cell lymphomagenesis in immunosuppressed patients, and validate a new therapeutic approach. º In mice, the EBV protein LMP1 induces B cell ablation through immune surveillance º Upon ablation of T cells, LMP1-driven lymphomas rapidly arise º These lymphomas model EBV-driven lymphomas in immunosuppressed patients º Stress antigens on these tumors can serve as targets of NK cell receptor therapy In immunosuppressed patients, Epstein-Barr virus frequently causes B cell lymphomas. The making of a mouse model for this disorder sheds light on its molecular underpinnings and is used in developing a potential therapy based on tumor recognition by natural killer cells.