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

Lim, Jia Jia, Jones, Claerwen M, Loh, Tiing Jen, Dao, Hien Thy, Tran, Mai T, Tye-Din, Jason A, La Gruta, Nicole L and Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 2025. A naturally selected αβ T cell receptor binds HLA-DQ2 molecules without co-contacting the presented peptide. Nature Communications 16 (1) , 3330. 10.1038/s41467-025-58690-w

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: Title: cc by, Type: cc by
Publisher:	Nature Research
ISSN:	2041-1723
Date of First Compliant Deposit:	22 April 2025
Date of Acceptance:	1 April 2025
Last Modified:	22 Apr 2025 11:30
URI:	https://orca.cardiff.ac.uk/id/eprint/177816

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