Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers

Fulford, TS; Soliman, C; Castle, RG; Rigau, M; Ruan, Z; Dolezal, O; Seneviratna, R; Brown, HG; Hanssen, E; Hammet, A; Li, S; Redmond, SJ; Chung, A; Gorman, MA; Parker, MW; Patel, O; Peat, TS; Newman, J; Behren, A; Gherardin, NA; Godfrey, DI; Uldrich, AP

Author(s): Fulford, TS; Soliman, C; Castle, RG; Rigau, M; Ruan, Z; Dolezal, O; Seneviratna, R; Brown, HG; Hanssen, E; Hammet, A; Li, S; Redmond, SJ; Chung, A; Gorman, MA; Parker, MW; Patel, O; Peat, TS; Newman, J; Behren, A; Gherardin, NA; Godfrey, DI; Uldrich, AP;
Details: Publication Year 2024-08,Volume 25,Issue #8,Page 1355-1366
Journal Title: Nature Immunology
Publication Type: Research article
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.
Publisher: Springer Nature
Keywords: *Butyrophilins/metabolism/immunology/chemistry; *Receptors, Antigen, T-Cell, gamma-delta/immunology/metabolism; Humans; Protein Binding; Protein Multimerization; Antigens, CD/metabolism/immunology/chemistry; T-Lymphocytes/immunology/metabolism; Crystallography, X-Ray; Lymphocyte Activation/immunology; Models, Molecular; Intraepithelial Lymphocytes/immunology/metabolism
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41590-024-01892-z
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-08-29 04:21:44

Last Modified: 2024-08-29 04:22:02