The co-receptor BTLA negatively regulates human Vγ9Vδ2 T-cell proliferation: a potential way of immune escape for lymphoma cells

V gamma 9V delta 2 cells, the major gamma delta T-cell subset in human peripheral blood, represent a T-cell subset that displays reactivity against microbial agents and tumors. The biology of V gamma 9V delta 2 T cells remains poorly understood. We show herein that the interaction between B-and T-lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) is a major regulator of V gamma 9V delta 2 T-cell proliferation control. BTLA was strongly expressed at the surface of resting V gamma 9V delta 2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of V gamma 9V delta 2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. Our data also suggested that BTLA-HVEM might participate in the control of gamma delta T-cell differentiation. In addition, the proliferation of autologous gamma delta T cells after exposition to lymphoma cells was dramatically reduced through BTLA-HVEM interaction. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with V gamma 9V delta 2 T-cell proliferation. Moreover, BTLA stimulation of V gamma 9V delta 2 T cells appears as a new possible mechanism of immune escape by lymphoma cells.