Targeted Activation of Human Vγ9Vδ2-T Cells Controls Epstein-Barr Virus-Induced B Cell Lymphoproliferative Disease

Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) after transplantation remains a serious and life-threatening complication. Herein we showed that the aminobisphosphonate pamidronate-expanded human Vγ9Vδ2-T cells efficiently killed EBV-transformed autologous lymphoblastoid B cell lines (EBV-LCL) through γ/δ-TCR and NKG2D receptor triggering and Fas and TRAIL engagement. By inoculation of EBV-LCL in Rag2−/−γc−/− mice and humanized mice, we established lethal EBV-LPD with characteristics close to those of the human disease. Adoptive transfer of pamidronate-expanded Vγ9Vδ2-T cells alone effectively prevented EBV-LPD in Rag2−/−γc−/− mice and induced EBV-LPD regression in EBV+ tumor-bearing Rag2−/−γc−/− mice. Pamidronate treatment inhibited EBV-LPD development in humanized mice through selective activation and expansion of Vγ9Vδ2-T cells. This study provides proof-of-principle for a therapeutic approach using pamidronate to control EBV-LPD through Vγ9Vδ2-T cell targeting. [Display omitted] •Pamidronate-expanded Vγ9Vδ2-T cells kill EBV-LCL by engagement of Fas and TRAIL•The killing of Vγ9Vδ2-T cells requires both TCR and NKG2D receptor triggering•Adoptive transfer of Vγ9Vδ2-T cells prevents EBV-LPD and induces its regression•Pamidronate controls EBV-LPD by boosting Vγ9Vδ2-T cell immunity Epstein-Barr virus-induced lymphoproliferative disease (EBV-LPD) in immunocompromised patients is a serious condition with limited treatment options. Xiang et al. provide proof-of-principle that the aminobisphosphonate pamidronate can effectively control EBV-LPD by enhancing Vγ9Vδ2-T-cell immunity.