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Cited by 57T-cell and B-cell Immunologyvaccines and immunoinformatics approachesPsoriasis: Treatment and Pathogenesis

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Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

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Fulford, Thomas S., Soliman, Caroline, Castle, Rebecca G., Rigau, Marc, Ruan, Zheng, Dolezal, Olan, Seneviratna, Rebecca, Brown, Hamish G., Hanssen, Eric, Hammet, Andrew, Li, Shihan, Redmond, Samuel J., Chung, Amy, Gorman, Michael A., Parker, Michael W., Patel, Onisha, Peat, Thomas S., Newman, Janet, Behren, Andreas, Gherardin, Nicholas A., Godfrey, Dale I., Uldrich, Adam P.·2024·Nature Immunology
DOI 10.1038/s41590-024-01892-z

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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 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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Metadata

Authors
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.
Affiliations
  • The University of Melbourne (AU)
  • University of Bonn (DE)
  • Commonwealth Scientific and Industrial Research Organisation (AU)
  • CSL (Australia) (AU)
Corresponding author
  • Godfrey, Dale I.
  • Uldrich, Adam P.
ORCID
Venue
Nature Immunology
Publisher
Springer Science and Business Media LLC
Published
2024-07-16
Volume
25
Issue
8
Pages
1355-1366
ISSN
  • 1529-2908 (ISSN-L)
  • 1529-2916
DOI
10.1038/s41590-024-01892-z
OpenAlex
W4400689609
Cited by
57
References
2
Citations by year
2026: 26 · 2025: 25 · 2024: 6
FWCI
9.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Immunology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion)
  • Griffith Research Online (submittedVersion, other-oa)
Funders
  • Department of Health | National Health and Medical Research Council (1184906, 1165467, 1117766, 2008913, 1194263)
  • Cancer Council Victoria (1126866)
  • Department of Education and Training | Australian Research Council (DP230102753, CE140100011, DE210100705)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
  • Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
Keywords
Vγ9Vδ2 T cells, butyrophilin, BTN2A1, BTN3A1, T cell receptor stimulation, crystal structure, T cell immunity
MeSH terms
Butyrophilins, Intraepithelial Lymphocytes, Humans, Lymphocyte Activation, Models, Molecular, Protein Binding, T-Lymphocytes, Antigens, CD, Receptors, Antigen, T-Cell, gamma-delta, Crystallography, X-Ray, Protein Multimerization

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