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

作者：Christelle Harly, Yves Claude Guillaume, Steven Nédellec, Cassie-Marie Peigné, Hannu Mönkkönen, Jukka Mönkkönen, Jianqiang Li, Jurgen H. E. Kuball, Erin J. Adams, Sonia Netzer, Julie Déchanet‐Merville, Alexandra Léger, Thomas RW Herrmann, Richard Breathnach, Daniel Olive, Marc Bonneville, Emmanuel Scotet · 发表于：Blood · 年份：2012 · DOI：10.1182/blood-2012-05-430470 · 被引用次数：547 · 研究领域：T-cell and B-cell Immunology、Immune Cell Function and Interaction、CAR-T cell therapy research

Human peripheral Vγ9Vδ2 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 Vγ9Vδ2 T-cell activation and that the Vγ9Vδ2 T-cell receptor is implicated in this effect. Vγ9Vδ2 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 Vγ9Vδ2 T cells. Fluorescence recovery after photobleaching (FRAP) experiments support a causal link between intracellular PAg accumulation, decreased BTN3A1 membrane mobility, 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.