Journal article
Structure of a fully assembled γδ T-cell antigen receptor
- Abstract:
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T cells in jawed vertebrates comprise two lineages, αβ T-cells and γδ T-cells, defined by the antigen receptors they express, i.e., αβ and γδ T-cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring γδ TCRs to recognize more structurally-diverse ligands1. Nevertheless, the receptors use shared CD3 subunits to initiate signaling. Whereas the structural organization of αβ TCRs is understood2,3, the architecture of γδ TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully-assembled, MR1-reactive human Vδ3Vγ8 TCR/CD3δγε2ζ2 complex bound by anti-CD3ε antibody Fab fragments4,5. The arrangement of CD3 subunits in γδ and αβ TCRs is conserved and, although the transmembrane α-helices of the TCR-γδ and -αβ subunits differ markedly in sequence, the packing of the eight transmembrane-helix bundles is similar6. However, in contrast to the apparently rigid αβ TCR2,3,6, the γδ TCR exhibits considerable conformational heterogeneity, owing to the ligand-binding TCR-γδ subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transferring the Vδ3Vγ8 TCR variable domains to an αβ TCR enhanced receptor signaling, suggesting that γδ TCR organization reflects a compromise between efficient signaling and the ability to engage structurally-diverse ligands. Our findings reveal the remarkable structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signaling as either a rigid or flexible structure.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Files:
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(Preview, Version of record, pdf, 32.4MB, Terms of use)
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- Publisher copy:
- 10.1038/s41586-024-07920-0
Authors
- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- 207547/Z/17/Z
- Funder identifier:
- https://ror.org/054225q67
- Grant:
- DRCCIPA\100010
- Publisher:
- Springer Nature
- Journal:
- Nature More from this journal
- Volume:
- 634
- Issue:
- 8034
- Pages:
- 729-736
- Publication date:
- 2024-08-15
- Acceptance date:
- 2024-08-07
- DOI:
- EISSN:
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1476-4687
- ISSN:
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0028-0836
- Pmid:
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39146975
- Language:
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English
- Keywords:
- Pubs id:
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2022125
- Local pid:
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pubs:2022125
- Deposit date:
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2024-09-14
Terms of use
- Copyright holder:
- Gully et al.
- Copyright date:
- 2024
- Rights statement:
- Copyright © 2024, The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
- Licence:
- CC Attribution (CC BY)
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