TY - JOUR
T1 - Prevention of Vγ9Vδ2 T cell activation by a Vγ9Vδ2 TCR nanobody
AU - De Bruin, Renée C.G.
AU - Stam, Anita G.M.
AU - Vangone, Anna
AU - Van Bergen En Henegouwen, Paul M.P.
AU - Verheul, Henk M.W.
AU - Sebestyén, Zsolt
AU - Kuball, Jürgen
AU - Bonvin, Alexandre M.J.J.
AU - De Gruijl, Tanja D.
AU - Van Der Vliet, Hans J.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85007007572&partnerID=8YFLogxK
U2 - https://doi.org/10.4049/jimmunol.1600948
DO - https://doi.org/10.4049/jimmunol.1600948
M3 - Article
C2 - 27895170
SN - 0022-1767
VL - 198
SP - 308
EP - 317
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -