Key implication of CD277/butyrophilin-3 (BTN3A) in cellular stress sensing by a major human γδ T-cell subset.

Human peripheral Vγ9Vδ2 T cells are acti-vated by phosphorylated metabolites (phosphoagonists [PAg]) of the mam-malian mevalonate or the microbial desoxyxylulose-phosphate pathways ac-cumulated by infected or metabolically distressed cells. The underlying mecha-nisms are unknown. We show that treat-ment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced Vγ9Vδ2 T-cell activation and that the Vγ9Vδ2 T-cell receptor is implicated in this effect. Vγ9Vδ2 T-cell activation can be abro-gated by exposing susceptible cells (tu-mor and mycobacteria-infected cells, or aminobisphosphonate-treated cells with up-regulated PAg levels) to antibody 103.2 against CD277. CD277 knockdown and domain-shuffling approaches confirm the key implication of the CD277 isoform BTN3A1 in PAg sensing by Vγ9Vδ2 T cells. Fluorescence recovery after photobleaching (FRAP) experiments support a causal link between intracellular PAg accumula-tion, decreased BTN3A1 membrane mobil-ity, and ensuing Vγ9Vδ2 T-cell activation. This study demonstrates a novel role played by B7-like molecules In human γδ T-cell antigenic activation and paves the way for new strategies to improve the efficiency of immunotherapies using Vγ9Vδ2 T cells. [ABSTRACT FROM AUTHOR]