Human Vγ9Vδ2 T cells recognize in a butyrophilin 3A/CD277–dependent way microbial (E)-4-hydroxy-3-methyl-but-2-enyl
pyrophosphate (HMBPP) or endogenous pyrophosphates (isopentenyl
pyrophosphate [IPP]). Nitrogen-bisphosphonates
such as zoledronic acid (ZOL) trigger selective
γδ T cell activation because they stimulate IPP production in monocytes
by
inhibiting the mevalonate pathway downstream of
IPP synthesis. We performed a comparative analysis of the capacity of
purified
monocytes, neutrophils, and CD4 T cells to serve
as accessory cells for Vγ9Vδ2 T cell activation in response to three
selective
but mechanistically distinct stimuli (ZOL,
HMBPP, agonistic anti-CD277 mAb). Only monocytes supported γδ T cell
expansion
in response to all three stimuli, whereas both
neutrophils and CD4 T cells presented HMBPP but failed to induce γδ T
cell
expansion in the presence of ZOL or anti-CD277
mAb. Preincubation of accessory cells with the respective stimuli
revealed
potent γδ T cell–stimulating activity of ZOL- or
anti-CD277 mAb-pretreated monocytes, but not neutrophils. In comparison
with
monocytes, ZOL-pretreated neutrophils produced
little, if any, IPP and expressed much lower levels of farnesyl
pyrophosphate
synthase. Exogenous IL-18 enhanced the γδ T cell
expansion with all three stimuli, remarkably also in response to CD4 T
cells
and neutrophils preincubated with anti-CD277 mAb
or HMBPP. Our study uncovers unexpected differences between monocytes
and
neutrophils in their accessory function for
human γδ T cells and underscores the important role of IL-18 in driving
γδ T cell
expansion. These results may have implications
for the design of γδ T cell–based immunotherapeutic strategies.