Vγ2Vδ2 T-cell receptor–mediated recognition of aminobisphosphonates

Abstract

Aminobisphosphonates, potent derivatives of bisphosphonates, are frequently used for the treatment of conditions such as osteoporosis and bone metastases that are characterized by excessive osteoclastic bone resorption. Using T-cell receptor (TCR) transfer studies, we show that recognition of antigenic aminobisphosphonates that are known to stimulate human γδ T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vγ2Vδ2 TCR and is thus Vγ2Vδ2 TCR–dependent. Myeloma cells or monocytes pulsed with risedronate and then washed rendered these target cells sensitive to lysis by a Vγ2Vδ2 T-cell clone or cell line. These results suggest that Vγ2Vδ2 TCR–dependent recognition leading to direct cytolysis of aminobisphosphonate-sensitized osteoclast or tumor targets may be a mechanism whereby aminobisphosphonate treatment of cancers metastatic to bone decreases osteoclastic activity and tumor burden and also may account for the decreased osteoclastic activity associated with successful treatment of osteoporosis.