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Blood. 2013 Aug 8;122(6):922-31. doi: 10.1182/blood-2012-11-464685. Epub 2013 May 21.

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

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Institut National de la Santé et de la Recherche Scientifique, U1068, Centre de Recherche en Cancérologie de Marseille-Immunity & Cancer, 27 Bd Lei Roure, Marseille, France.


Vγ9Vδ2 cells, the major γδ T-cell subset in human peripheral blood, represent a T-cell subset that displays reactivity against microbial agents and tumors. The biology of Vγ9Vδ2 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 Vγ9Vδ2 T-cell proliferation control. BTLA was strongly expressed at the surface of resting Vγ9Vδ2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vγ9Vδ2 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 γδ T-cell differentiation. In addition, the proliferation of autologous γδ 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 Vγ9Vδ2 T-cell proliferation. Moreover, BTLA stimulation of Vγ9Vδ2 T cells appears as a new possible mechanism of immune escape by lymphoma cells.

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