title: Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody.
abstract: Vγ9Vδ2 T cell activation plays an important role in antitumor and antimicrobial immune responses. However, there are conditions in which Vγ9Vδ2 T cell activation can be considered inappropriate for the host. Patients treated with aminobisphosphonates for hypercalcemia or metastatic bone disease often present with a debilitating acute phase response as a result of Vγ9Vδ2 T cell activation. To date, no agents are available that can clinically inhibit Vγ9Vδ2 T cell activation. In this study, we describe the identification of a single domain Ab fragment directed to the TCR of Vγ9Vδ2 T cells with neutralizing properties. This variable domain of an H chain-only Ab (VHH or nanobody) significantly inhibited both phosphoantigen-dependent and -independent activation of Vγ9Vδ2 T cells and, importantly, strongly reduced the production of inflammatory cytokines upon stimulation with aminobisphosphonate-treated cells. Additionally, in silico modeling suggests that the neutralizing VHH binds the same residues on the Vγ9Vδ2 TCR as the Vγ9Vδ2 T cell Ag-presenting transmembrane protein butyrophilin 3A1, providing information on critical residues involved in this interaction. The neutralizing Vγ9Vδ2 TCR VHH identified in this study might provide a novel approach to inhibit the unintentional Vγ9Vδ2 T cell activation as a consequence of aminobisphosphonate administration.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
authors.forename: Renée C G
authors.initials: RC
authors.lastname: de Bruin
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
authors.forename: Anita G M
authors.initials: AG
authors.lastname: Stam
authors.affiliation: Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Anna
authors.identifier: 0000-0003-2485-7378
authors.initials: A
authors.lastname: Vangone
authors.affiliation: Department of Cell Biology, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands; and.
authors.forename: Paul M P
authors.identifier: 0000-0001-6050-9042
authors.initials: PM
authors.lastname: van Bergen En Henegouwen
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
authors.forename: Henk M W
authors.initials: HM
authors.lastname: Verheul
authors.affiliation: Laboratory of Translational Immunology, Department of Hematology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Sebestyén
authors.affiliation: Laboratory of Translational Immunology, Department of Hematology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kuball
authors.affiliation: Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, 3584 CH Utrecht, the Netherlands.
authors.forename: Alexandre M J J
authors.identifier: 0000-0001-7369-1322
authors.initials: AM
authors.lastname: Bonvin
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands.
authors.forename: Tanja D
authors.initials: TD
authors.lastname: de Gruijl
authors.affiliation: Department of Medical Oncology, VU University Medical Center, 1081 HV Amsterdam, the Netherlands; jj.vandervliet@vumc.nl.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: van der Vliet
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D018448:Models, Immunological; D062105:Molecular Docking Simulation; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000037:antagonists & inhibitors* / Q000276:immunology; D057127:Single-Chain Antibodies / Q000276:immunology / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D057134:Antibodies, Neutralizing; D016692:Receptors, Antigen, T-Cell, gamma-delta; D057127:Single-Chain Antibodies