Abstract
Aminobisphosphonates, synthetic analogues of endogenous pyrophosphate, have been widely used for the treatment of osteoporosis and bone metastases characterized by excessive osteoclastic bone resorption. Such aminobisphosphonates can be recognized by human γδ T cells having inherent Vγ2Vδ2 T cell receptors (TCRs) circulating in the blood. Here we show that risedronate, one of the most potent aminobisphosphonates, together with 10 U/ml IL-2, strongly expanded both CD8αα-positive and double negative Vγ2Vδ2 T cells among freshly isolated peripheral blood mononuclear cells (PBMCs) from healthy individuals in vitro. The optimal concentration of risedronate was 5 μM and the expanded Vγ2Vδ2 T cells secreted a good amount of IFN-γ as well as small amount of TNF-α but not IL-4. Complete abrogation of IFN-γ production was observed in Vδ2-depleted PBMCs when stimulated with 5 μM of risedronate for 7 days. However, oral administration with risedronate had no effect on the absolute number of Vγ2Vδ2 T cells in PBMCs and risedronate medication for 8 weeks did not prime those γδ T cells for proliferation by in vitro restimulation. Nonetheless, we did observe transient enhancement of IFN-γ production in the supernatant 48 h after the risedronate stimulation among 3 out of 6 patients on either two or four weeks after the medication. These data suggest that orally administered risedronate can commit Vγ2Vδ2-positive γδ T cells to IFN-γ-secreting effectors in vivo.
