The majority of human γδ T cells express Vγ2Vδ2 TCRs and play important roles in microbial and tumor immunity. Vγ2Vδ2 T cells use their TCRs to recognize self and foreign prenyl pyrophosphate intermediates (prenyl-PP) in isoprenoid synthesis. However, little is known about the molecular basis for this recognition. We find that a monoclonal antibody specific for butyrophillin 3 (BTN3) Ig superfamily proteins mimics prenyl-PPs. The 20.1 mAb stimulated Vγ2Vδ2 T cell clones regardless of their functional phenotype or developmental origin, and selectively expanded blood Vγ2Vδ2 T cells. The γδ TCR mediates 20.1 stimulation since IL-2 is released by β− Jurkat cells transfected with Vγ2Vδ2 TCRs. 20.1 stimulation was not due isopentenyl pyrophosphate (IPP) accumulation because 20.1 treatment of APC did not increase IPP levels. Nor was stimulation inhibited by statin treatment which blocks IPP production. Importantly, siRNA knockdown of BTN3A1 abolished stimulation by IPP that could be restored by re-expressing BTN3A1. Rhesus monkey and baboon APC presented IPP and 20.1 to human Vγ2Vδ2 T cells despite amino acid differences localized to the outer BTN3A1 face suggesting that the top and/or the inner face interact with its co-receptor. Full length BTN3A1 did not preferentially bind a photoaffinity prenyl-PP analog. Our results confirm and extend recent studies and demonstrate that BTN3A1 is required for the recognition of prenyl-PP but does not appear to bind the intermediates directly.
- Copyright © 2013 by The American Association of Immunologists, Inc.