Prevention of Vγ9Vδ2 T Cell Activation by a Vγ9Vδ2 TCR Nanobody

V gamma 9V delta 2 T cell activation plays an important role in antitumor and antimicrobial immune responses. However, there are conditions in which V gamma 9V delta 2 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 V gamma 9V delta 2 T cell activation. To date, no agents are available that can clinically inhibit V gamma 9V delta 2 T cell activation. In this study, we describe the identification of a single domain Ab fragment directed to the TCR of V gamma 9V delta 2 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 V gamma 9V delta 2 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 V gamma 9V delta 2 TCR as the V gamma 9V delta 2 T cell Ag-presenting transmembrane protein butyrophilin 3A1, providing information on critical residues involved in this interaction. The neutralizing Vg9Vd2 TCR VHH identified in this study might provide a novel approach to inhibit the unintentional V gamma 9V delta 2 T cell activation as a consequence of aminobisphosphonate administration.