Vgamma9Vdelta2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Fulford, T. S.; Soliman, C.; Castle, R. G.; Rigau, M.; Ruan, Z.; Dolezal, O.; Seneviratna, R.; Brown, H. G.; Hanssen, E.; Hammet, A.; Li, S.; Redmond, S. J.; Chung, A.; Gorman, M. A.; Parker, M. W.; Patel, O.; Peat, T. S.; Newman, J.; Behren, A.; Gherardin, N. A.; Godfrey, D. I.; Uldrich, A. P.

doi:10.1101/2023.08.30.555639

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bioRxiv · 10.1101/2023.08.30.555639

Vgamma9Vdelta2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

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Abstract

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity, however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell receptor ({gamma}{delta}TCR) in complex with BTN member 2A1 (BTN2A1) revealed that BTN2A1 engages the side of the {gamma}{delta}TCR, leaving the apical TCR surface bioavailable. We reveal that BTN3A1 is a second {gamma}{delta}TCR ligand, that co-engages {gamma}{delta}TCR via binding to this accessible apical surface. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1-BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to engage {gamma}{delta}TCR; indeed, either forced separation or locking together of BTN2A1 and BTN3A1 resulted in enhanced or abrogated {gamma}{delta}TCR interaction, respectively. Our findings reveal a new paradigm in immune activation, whereby {gamma}{delta}TCRs recognize dual epitopes on BTN2A1 and BTN3A1 complexes.

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Fulford, T. S., Soliman, C., Castle, R. G., Rigau, M., Ruan, Z., Dolezal, O., Seneviratna, R., Brown, H. G., Hanssen, E., Hammet, A., Li, S., Redmond, S. J., Chung, A., Gorman, M. A., Parker, M. W., Patel, O., Peat, T. S., Newman, J., Behren, A., Gherardin, N. A., Godfrey, D. I., Uldrich, A. P.. 2023-09-01. Vgamma9Vdelta2 T cells recognize butyrophilin 2A1 and 3A1 heteromers. https://doi.org/10.1101/2023.08.30.555639

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