Butyrophilin-2A1 directly binds germline-encoded regions of the Vγ9Vδ2 TCR and is essential for phosphoantigen sensing

Mohindar M. Karunakaran, Carrie R. Willcox, Mahboob Salim, Daniel Paletta, Alina S. Fichtner, Angela Noll, Lisa Starick, Anna Nöhren, Charlotte R. Begley, Katie A. Berwick, Raphaël A.g. Chaleil, Vincent Pitard, Julie Déchanet-merville, Paul A. Bates, Brigitte Kimmel, Timothy J. Knowles, Volker Kunzmann, Lutz Walter, Mark Jeeves, Fiyaz MohammedBenjamin E. Willcox, Thomas Herrmann

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44 Citations (Scopus)
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Vγ9Vδ2 T cells respond in a TCR-dependent fashion to both microbial and host-derived pyrophosphate compounds (phosphoantigens, or P-Ag). Butyrophilin-3A1 (BTN3A1), a protein structurally related to the B7 family of costimulatory molecules, is necessary but insufficient for this process. We performed radiation hybrid screens to uncover direct TCR ligands and cofactors that potentiate BTN3A1's P-Ag sensing function. These experiments identified butyrophilin-2A1 (BTN2A1) as essential to Vγ9Vδ2 T cell recognition. BTN2A1 synergised with BTN3A1 in sensitizing P-Ag-exposed cells for Vγ9Vδ2 TCR-mediated responses. Surface plasmon resonance experiments established Vγ9Vδ2 TCRs used germline-encoded Vγ9 regions to directly bind the BTN2A1 CFG-IgV domain surface. Notably, somatically recombined CDR3 loops implicated in P-Ag recognition were uninvolved. Immunoprecipitations demonstrated close cell-surface BTN2A1-BTN3A1 association independent of P-Ag stimulation. Thus, BTN2A1 is a BTN3A1-linked co-factor critical to Vγ9Vδ2 TCR recognition. Furthermore, these results suggest a composite-ligand model of P-Ag sensing wherein the Vγ9Vδ2 TCR directly interacts with both BTN2A1 and an additional ligand recognized in a CDR3-dependent manner.
Original languageEnglish
Pages (from-to)487-498.e6
Number of pages18
Issue number3
Early online date9 Mar 2020
Publication statusPublished - 17 Mar 2020


  • T cell receptor
  • Vγ9Vδ2
  • butyrophilin
  • complementarity-determining region
  • gamma delta T cell
  • ligand
  • phosphoantigen

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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