Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

doi:10.1038/s41590-024-01892-z

. 2024 Aug;25(8):1355-1366.

doi: 10.1038/s41590-024-01892-z. Epub 2024 Jul 16.

Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Thomas S Fulford¹, Caroline Soliman¹, Rebecca G Castle¹, Marc Rigau^{1

2

3}, Zheng Ruan¹, Olan Dolezal⁴, Rebecca Seneviratna¹, Hamish G Brown⁵, Eric Hanssen^{5

6

7}, Andrew Hammet⁸, Shihan Li¹, Samuel J Redmond¹, Amy Chung¹, Michael A Gorman⁶, Michael W Parker^{6

7

9}, Onisha Patel^{10

11}, Thomas S Peat⁴, Janet Newman⁴, Andreas Behren^{12

13}, Nicholas A Gherardin¹, Dale I Godfrey¹⁴, Adam P Uldrich^{15

16}

Affiliations

¹ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
² Institute of Molecular Medicine and Experimental Immunology, Rheinische Friedrichs-Wilhelms University of Bonn, Bonn, Germany.
³ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Parkville, Victoria, Australia.
⁵ Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
⁶ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
⁷ ARC Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins, University of Melbourne, Parkville, Victoria, Australia.
⁸ CSL Limited, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia.
⁹ St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
¹⁰ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹¹ Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
¹² Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
¹³ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
¹⁴ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. godfrey@unimelb.edu.au.
¹⁵ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. auldrich@unimelb.edu.au.
¹⁶ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. auldrich@unimelb.edu.au.

PMID: 39014161
DOI: 10.1038/s41590-024-01892-z

Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Thomas S Fulford et al. Nat Immunol. 2024 Aug.

. 2024 Aug;25(8):1355-1366.

doi: 10.1038/s41590-024-01892-z. Epub 2024 Jul 16.

Authors

Affiliations

¹ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia.
² Institute of Molecular Medicine and Experimental Immunology, Rheinische Friedrichs-Wilhelms University of Bonn, Bonn, Germany.
³ Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
⁴ Biomedical Manufacturing, Commonwealth Scientific and Industrial Research Organisation, Parkville, Victoria, Australia.
⁵ Ian Holmes Imaging Centre, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
⁶ Department of Biochemistry and Pharmacology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Victoria, Australia.
⁷ ARC Industrial Transformation Training Centre for Cryo-electron Microscopy of Membrane Proteins, University of Melbourne, Parkville, Victoria, Australia.
⁸ CSL Limited, Bio21 Molecular Science and Biotechnology Institute, Parkville, Victoria, Australia.
⁹ St. Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
¹⁰ The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
¹¹ Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
¹² Olivia Newton-John Cancer Research Institute, and School of Cancer Medicine, La Trobe University, Heidelberg, Victoria, Australia.
¹³ Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.
¹⁴ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. godfrey@unimelb.edu.au.
¹⁵ Department of Microbiology & Immunology at the Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. auldrich@unimelb.edu.au.
¹⁶ Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. auldrich@unimelb.edu.au.

PMID: 39014161
DOI: 10.1038/s41590-024-01892-z

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 antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner. 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 mediate the γδTCR interaction; indeed, locking BTN2A1 and BTN3A1 together abrogated their interaction with γδTCR, supporting a model wherein the two γδTCR ligand-binding sites depend on accessibility to cryptic BTN epitopes. Our findings reveal a new paradigm in immune activation, whereby γδTCRs sense dual epitopes on BTN complexes.

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Cited by

The Evolving Portrait of γδ TCR Recognition Determinants.
Sok CL, Rossjohn J, Gully BS. Sok CL, et al. J Immunol. 2024 Sep 1;213(5):543-552. doi: 10.4049/jimmunol.2400114. J Immunol. 2024. PMID: 39159405 Review.

References

1. Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021). - DOI - PubMed
1. Constant, P. et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994). - DOI - PubMed
1. Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375, 155–158 (1995). - DOI - PubMed
1. Tyler, C. J., Doherty, D. G., Moser, B. & Eberl, M. Human Vγ9/Vδ2 T cells: innate adaptors of the immune system. Cell Immunol. 296, 10–21 (2015). - DOI - PubMed
1. Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018). - DOI - PubMed - PMC

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[1] Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021). - DOI - PubMed

[2] Ribot, J. C., Lopes, N. & Silva-Santos, B. γδ T cells in tissue physiology and surveillance. Nat. Rev. Immunol. 21, 221–232 (2021). - DOI - PubMed

[3] Constant, P. et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994). - DOI - PubMed

[4] Constant, P. et al. Stimulation of human gamma delta T cells by nonpeptidic mycobacterial ligands. Science 264, 267–270 (1994). - DOI - PubMed

[5] Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375, 155–158 (1995). - DOI - PubMed

[6] Tanaka, Y. et al. Natural and synthetic non-peptide antigens recognized by human gamma delta T cells. Nature 375, 155–158 (1995). - DOI - PubMed

[7] Tyler, C. J., Doherty, D. G., Moser, B. & Eberl, M. Human Vγ9/Vδ2 T cells: innate adaptors of the immune system. Cell Immunol. 296, 10–21 (2015). - DOI - PubMed

[8] Tyler, C. J., Doherty, D. G., Moser, B. & Eberl, M. Human Vγ9/Vδ2 T cells: innate adaptors of the immune system. Cell Immunol. 296, 10–21 (2015). - DOI - PubMed

[9] Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018). - DOI - PubMed - PMC

[10] Hoeres, T., Smetak, M., Pretscher, D. & Wilhelm, M. Improving the efficiency of Vγ9Vδ2 T-cell immunotherapy in cancer. Front. Immunol. 9, 800 (2018). - DOI - PubMed - PMC

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Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

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Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

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