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

Human peripheral V gamma 9V delta 2 T cells are activated by phosphorylated metabolites (phosphoagonists [PAg]) of the mammalian mevalonate or the microbial desoxyxylulose-phosphate pathways accumulated by infected or metabolically distressed cells. The underlying mechanisms are unknown. We show that treatment of nonsusceptible target cells with antibody 20.1 against CD277, a member of the extended B7 superfamily related to butyrophilin, mimics PAg-induced V gamma 9V delta 2 T-cell activation and that the V gamma 9V delta 2 T-cell receptor is implicated in this effect. V gamma 9V delta 2 T-cell activation can be abrogated by exposing susceptible cells (tumor 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 V gamma 9V delta 2 T cells. Fluorescence recovery after photobleach-ing (FRAP) experiments support a causal link between intracellular PAg accumulation, decreased BTN3A1 membrane mobility, and ensuing V gamma 9V delta 2 T-cell activation. This study demonstrates a novel role played by B7-like molecules in human gamma delta T-cell antigenic activation and paves the way for new strategies to improve the efficiency of immunotherapies using V gamma 9V delta 2 T cells. (Blood. 2012;120(11):2269-2279)