Key Implication of CD277/butyrophilin-3 (BTN3A) in Cellular Stress Sensing by a Major Human γδ T-cell Subset

Blood. 2012 Sep 13;120(11):2269-79. doi: 10.1182/blood-2012-05-430470. Epub 2012 Jul 5.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Blocking
  • Antibodies, Immobilized
  • Antibodies, Monoclonal
  • Antigens / metabolism*
  • Antigens, CD / chemistry
  • Antigens, CD / genetics
  • Antigens, CD / metabolism*
  • Butyrophilins
  • Cells, Cultured
  • Clone Cells
  • Enzyme Inhibitors / pharmacology
  • HEK293 Cells
  • Humans
  • Immunologic Factors / pharmacology
  • Lymphocyte Activation* / drug effects
  • Phosphorylation / drug effects
  • Protein Isoforms / agonists
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Processing, Post-Translational / drug effects
  • Protein Transport / drug effects
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell / agonists
  • Receptors, Antigen, T-Cell / antagonists & inhibitors
  • Receptors, Antigen, T-Cell / metabolism*
  • Recombinant Proteins / agonists
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • T-Lymphocyte Subsets / cytology
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*

Substances

  • Antibodies, Blocking
  • Antibodies, Immobilized
  • Antibodies, Monoclonal
  • Antigens
  • Antigens, CD
  • BTN3A1 protein, human
  • Butyrophilins
  • Enzyme Inhibitors
  • Immunologic Factors
  • Protein Isoforms
  • RNA, Small Interfering
  • Receptors, Antigen, T-Cell
  • Recombinant Proteins