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

Jia Jia Lim, Claerwen M. Jones, Tiing Jen Loh, Hien Thy Dao, Mai T. Tran, Jason A. Tye-Din, Nicole L. Gruta () and Jamie Rossjohn ()
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Jia Jia Lim: Monash University
Claerwen M. Jones: Monash University
Tiing Jen Loh: Monash University
Hien Thy Dao: Monash University
Mai T. Tran: Monash University
Jason A. Tye-Din: The Walter and Eliza Hall Institute
Nicole L. Gruta: Monash University
Jamie Rossjohn: Monash University

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58690-w

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