Butyrophilin-like 3 directly binds a human Vγ4+ t cell receptor using a modality distinct from clonally-restricted antigen

Carrie Willcox, Pierre Vantourout, Mahboob Salim, Iva Zlatareva, Daisy Melandri, Leonor Zanardo, Roger George, Svend Kjaer, Mark Jeeves, Fiyaz Mohammed, Adrian C Hayday, Benjamin Willcox

Research output: Contribution to journalArticlepeer-review

41 Citations (Scopus)
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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.
Original languageEnglish
Pages (from-to)813-825.e4
Issue number5
Early online date15 Oct 2019
Publication statusPublished - 19 Nov 2019


  • butyrophilin
  • gamma delta T cell
  • T cell receptor
  • complementarity determining region
  • ligand
  • selection


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