Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Blocking
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Antibodies, Immobilized
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Antibodies, Monoclonal
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Antigens / metabolism*
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Antigens, CD / chemistry
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Antigens, CD / genetics
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Antigens, CD / metabolism*
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Butyrophilins
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Cells, Cultured
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Clone Cells
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Enzyme Inhibitors / pharmacology
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HEK293 Cells
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Humans
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Immunologic Factors / pharmacology
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Lymphocyte Activation* / drug effects
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Phosphorylation / drug effects
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Protein Isoforms / agonists
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Protein Isoforms / antagonists & inhibitors
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Processing, Post-Translational / drug effects
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Protein Transport / drug effects
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RNA, Small Interfering
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Receptors, Antigen, T-Cell / agonists
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Receptors, Antigen, T-Cell / antagonists & inhibitors
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Receptors, Antigen, T-Cell / metabolism*
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Recombinant Proteins / agonists
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / metabolism
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / drug effects
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism*
Substances
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Antibodies, Blocking
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Antibodies, Immobilized
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Antibodies, Monoclonal
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Antigens
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Antigens, CD
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BTN3A1 protein, human
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Butyrophilins
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Enzyme Inhibitors
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Immunologic Factors
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Protein Isoforms
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RNA, Small Interfering
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Receptors, Antigen, T-Cell
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Recombinant Proteins