Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells

Science. 2020 Feb 7;367(6478):eaay5516. doi: 10.1126/science.aay5516. Epub 2020 Jan 9.


Gamma delta (γδ) T cells are essential to protective immunity. In humans, most γδ T cells express Vγ9Vδ2+ T cell receptors (TCRs) that respond to phosphoantigens (pAgs) produced by cellular pathogens and overexpressed by cancers. However, the molecular targets recognized by these γδTCRs are unknown. Here, we identify butyrophilin 2A1 (BTN2A1) as a key ligand that binds to the Vγ9+ TCR γ chain. BTN2A1 associates with another butyrophilin, BTN3A1, and these act together to initiate responses to pAg. Furthermore, binding of a second ligand, possibly BTN3A1, to a separate TCR domain incorporating Vδ2 is also required. This distinctive mode of Ag-dependent T cell activation advances our understanding of diseases involving pAg recognition and creates opportunities for the development of γδ T cell-based immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD / chemistry
  • Antigens, CD / immunology
  • Antigens, Neoplasm / immunology*
  • Butyrophilins / chemistry
  • Butyrophilins / genetics
  • Butyrophilins / immunology*
  • Cell Line, Tumor
  • Humans
  • Ligands
  • Lymphocyte Activation
  • Phosphorylation
  • Protein Domains
  • Protein Multimerization
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • T-Lymphocytes / immunology*


  • Antigens, CD
  • Antigens, Neoplasm
  • BTN2A1 protein, human
  • BTN3A1 protein, human
  • Butyrophilins
  • Ligands
  • Receptors, Antigen, T-Cell, gamma-delta
  • T-cell receptor Vdelta2, human
  • T-cell receptor Vgamma9, human