The immunological roles of human γδ-T cells in Epstein-Barr virus infection-induced diseases.

Abstract

Epstein-Barr virus (EBV) is a herpesvirus that latently infects human B cells in most individuals and a leading cause of several human malignancies, such as EBV-induced B cell lymphoproliferative disorders (EBV-LPD). Human Vγ9Vδ2-T cells represent a minor but crucial population in immune system and act as an important component of immune effector cells that contribute to immunosurveillance against viral infection. However, the immunological roles of Vγ9Vδ2-T cells in EBV infection and EBV-related disorders are not well studied and characterized. In our study, we demonstrated that phosphoantigen-activated human Vγ9Vδ2 -T cells have potent cytotoxic activity against EBV-transformed B lymphoblastoid cell lines (EBV-LCLs) through TCR γδ and NKG2D triggering, and FasL and TRAIL engagement. By targeting human Vγ9Vδ2-T cells, we further demonstrated that pamidronate can control EBV-LPD in humanized mice through boosting Vγ9Vδ2-T cell immunity. Furthermore, the human macrophage plays a very critical role in triggering the immune surveillance against the EBV infection. But, the relationship between the Vγ9Vδ2-T cells and macrophages is still unknown during EBV infection. Accordingly, our data showed that human Monocyte-driven-Macrophages (MDMs) could be infected by EBV. Subsequently, Vγ9Vδ2-T cells displayed potential cytotoxic activities against EBV-infected MDMs in vitro. Using the blocking experiment, the result demonstrated that special monoclonal antibodies against TCR γδ and NKG2D could significantly inhibit the killing of infected-MDMs by Vγ9Vδ2-T cells. Moreover, Vγ9Vδ2-T cells could impair viral replication in the infected-MDMs through producing IFN-γ. These findings provide proof-of-principle for a therapeutic approach using Vγ9Vδ2-T cells to control EBV infection and EBVassociated human malignancies.