Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates.
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 gammadelta T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vgamma2Vdelta2 TCR and is thus Vgamma2Vdelta2 TCR-dependent. Myeloma cells or monocytes pulsed with risedronate and then washed rendered these target cells sensitive to lysis by a Vgamma2Vdelta2 T-cell clone or cell line. These results suggest that Vgamma2Vdelta2 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.
Das
H
H
Lymphocyte Biology Section, Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Wang
L
L
Kamath
A
A
Bukowski
J F
JF
D019386:Alendronate / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D000941:Antigens / Q000737:chemistry; D002461:Cell Line, Transformed; D003602:Cytotoxicity, Immunologic; D004164:Diphosphonates / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D016694:Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D009000:Monocytes / Q000187:drug effects; D009101:Multiple Myeloma / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010024:Osteoporosis / Q000188:drug therapy; D000077268:Pamidronate; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D000068296:Risedronic Acid; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
D000941:Antigens; D004164:Diphosphonates; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma; D000068296:Risedronic Acid; D012968:Etidronic Acid; D000077268:Pamidronate; D019386:Alendronate