Butyrophilin-like 3 Directly Binds a Human Vγ4 + T Cell Receptor Using a Modality Distinct from Clonally-Restricted Antigen

Immunity. 2019 Nov 19;51(5):813-825.e4. doi: 10.1016/j.immuni.2019.09.006. Epub 2019 Oct 15.


Butyrophilin (BTN) and butyrophilin-like (BTNL/Btnl) heteromers are major regulators of human and mouse γδ T cell subsets, but considerable contention surrounds whether they represent direct γδ T cell receptor (TCR) ligands. We demonstrate that the BTNL3 IgV domain binds directly and specifically to a human Vγ4+ TCR, "LES" with an affinity (∼15-25 μM) comparable to many αβ TCR-peptide major histocompatibility complex interactions. Mutations in germline-encoded Vγ4 CDR2 and HV4 loops, but not in somatically recombined CDR3 loops, drastically diminished binding and T cell responsiveness to BTNL3-BTNL8-expressing cells. Conversely, CDR3γ and CDR3δ loops mediated LES TCR binding to endothelial protein C receptor, a clonally restricted autoantigen, with minimal CDR1, CDR2, or HV4 contributions. Thus, the γδ TCR can employ two discrete binding modalities: a non-clonotypic, superantigen-like interaction mediating subset-specific regulation by BTNL/BTN molecules and CDR3-dependent, antibody-like interactions mediating adaptive γδ T cell biology. How these findings might broadly apply to γδ T cell regulation is also examined.

Keywords: T cell receptor; butyrophilin; complementarity determining region; gamma delta T cell; ligand; selection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antigens / chemistry
  • Antigens / immunology*
  • Butyrophilins / chemistry
  • Butyrophilins / metabolism*
  • Cell Line
  • Clonal Selection, Antigen-Mediated / immunology*
  • Epitopes / immunology
  • Germ Cells / metabolism
  • Humans
  • Immunoglobulin Variable Region / chemistry
  • Immunoglobulin Variable Region / immunology
  • Immunoglobulin Variable Region / metabolism
  • Ligands
  • Mice
  • Protein Binding / immunology
  • Protein Interaction Domains and Motifs
  • Receptors, Antigen, T-Cell, gamma-delta / chemistry
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Structure-Activity Relationship
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*


  • Antigens
  • Butyrophilins
  • Epitopes
  • Immunoglobulin Variable Region
  • Ligands
  • Receptors, Antigen, T-Cell, gamma-delta