A naturally selected αβ T cell receptor binds HLA-DQ2 molecules without co-contacting the presented peptide

Lim, JJ; Jones, CM; Loh, TJ; Dao, HT; Tran, MT; Tye-Din, JA; La Gruta, NL; Rossjohn, J

Author(s): Lim, JJ; Jones, CM; Loh, TJ; Dao, HT; Tran, MT; Tye-Din, JA; La Gruta, NL; Rossjohn, J;
Details: Publication Year 2025-04-08,Volume 16,Issue #1,Page 3330
Journal Title: Nature Communications
Abstract: αβ T cell receptors (TCR) co-recognise peptide (p) antigens that are presented by major histocompatibility complex (MHC) molecules. While marked variations in TCR-p-MHC docking topologies have been observed from structural studies, the co-recognition paradigm has held fast. Using HLA-DQ2.5-peptide tetramers, here we identify a TRAV12-1(+)-TRBV5-1(+) G9 TCR from human peripheral blood that binds HLA-DQ2.5 in a peptide-agnostic manner. The crystal structures of TCR-HLA-DQ2.5-peptide complexes show that the G9 TCR binds HLA-DQ2.5 in a reversed docking topology without contacting the peptide, with the TCR contacting the β1 region of HLA-DQ2.5 and distal from the peptide antigen binding cleft. High-throughput screening of HLA class I and II molecules finds the G9 TCR to be pan-HLA-DQ2 reactive, with leucine-55 of HLA-DQ2.5 being a key determinant underpinning G9 TCR specificity excluding other HLA-II allomorphs. Consistent with the functional assays, the interactions of the G9 TCR and HLA-DQ2.5 precludes CD4 binding, thereby impeding T cell activation. Collectively, we describe a naturally selected αβTCR from human peripheral blood that deviates from the TCR-p-MHC co-recognition paradigm.
Publisher: Springer Nature
Keywords: Humans; *HLA-DQ Antigens/metabolism/immunology/chemistry/genetics; *Receptors, Antigen, T-Cell, alpha-beta/metabolism/chemistry/immunology/genetics; *Peptides/metabolism/immunology/chemistry; Protein Binding; Crystallography, X-Ray; Molecular Docking Simulation
Research Division(s): Immunology
PubMed ID: 40199885
Publisher's Version: https://doi.org/10.1038/s41467-025-58690-w
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-58690-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-05-05 08:40:19

Last Modified: 2025-05-05 08:40:35