Structure of a fully assembled γδ T cell antigen receptor

• 成果类型: Article
• 署名作者: Gully, Benjamin S.; Fernandes, Joao Ferreira; Gunasinghe, Sachith D.; Vuong, Mai T.; Lui, Yuan; Rice, Michael T.; Rashleigh, Liam; Lay, Chan-sien; Littler, Dene R.; Sharma, Sumana; Santos, Ana Mafalda; Venugopal, Hariprasad; Rossjohn, Jamie; Davis, Simon J.
• 署名单位: Monash University; Monash University; University of Oxford; University of Oxford; Cardiff University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4482
• DOI: 10.1038/s41586-024-07920-0
• 发表日期: 2024-10-17
• 关键词: cryo-em structure; crystal-structure; RECOGNITION; lymphocytes; complex; MODEL; core

摘要

T cells in jawed vertebrates comprise two lineages, alpha beta T cells and gamma delta T cells, defined by the antigen receptors they express-that is, alpha beta and gamma delta T cell receptors (TCRs), respectively. The two lineages have different immunological roles, requiring that gamma delta TCRs recognize more structurally diverse ligands1. Nevertheless, the receptors use shared CD3 subunits to initiate signalling. Whereas the structural organization of alpha beta TCRs is understood2,3, the architecture of gamma delta TCRs is unknown. Here, we used cryogenic electron microscopy to determine the structure of a fully assembled, MR1-reactive, human V gamma 8V delta 3 TCR-CD3 delta gamma epsilon 2 zeta 2 complex bound by anti-CD3 epsilon antibody Fab fragments4,5. The arrangement of CD3 subunits in gamma delta and alpha beta TCRs is conserved and, although the transmembrane alpha-helices of the TCR-gamma delta and -alpha beta subunits differ markedly in sequence, packing of the eight transmembrane-helix bundles is similar. However, in contrast to the apparently rigid alpha beta TCR2,3,6, the gamma delta TCR exhibits considerable conformational heterogeneity owing to the ligand-binding TCR-gamma delta subunits being tethered to the CD3 subunits by their transmembrane regions only. Reducing this conformational heterogeneity by transfer of the V gamma 8V delta 3 TCR variable domains to an alpha beta TCR enhanced receptor signalling, suggesting that gamma delta TCR organization reflects a compromise between efficient signalling and the ability to engage structurally diverse ligands. Our findings reveal the marked structural plasticity of the TCR on evolutionary timescales, and recast it as a highly versatile receptor capable of initiating signalling as either a rigid or flexible structure. Cryogenic electron microscopy determines the structure of a fully assembled, MR1-reactive, human V gamma 8V delta 3 TCR-CD3 delta gamma epsilon 2 zeta 2 complex bound by anti-CD3 epsilon antibody Fab fragments.