9EJH

Peptide-independent T cell receptor recognition of HLA-DQ2

Summary for 9EJH

• Entry DOI: 10.2210/pdb9ejh/pdb
• Related: 9EJG
• Descriptor: HLA class II histocompatibility antigen, DQ alpha 1 chain, MHC class II HLA-DQ-beta-1, HLA class II histocompatibility antigen gamma chain, ... (9 entities in total)
• Functional Keywords: t cell receptor, immune receptor, human leukocyte antigen, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 95529.61

Authors

Lim, J.J.,Loh, T.J.,Reid, H.H.,Rossjohn, J. (deposition date: 2024-11-27, release date: 2025-03-26, Last modification date: 2025-05-21)

Primary citation

Lim, J.J.,Jones, C.M.,Loh, T.J.,Dao, H.T.,Tran, M.T.,Tye-Din, J.A.,La Gruta, N.L.,Rossjohn, J.
A naturally selected alpha beta T cell receptor binds HLA-DQ2 molecules without co-contacting the presented peptide.
Nat Commun, 16:3330-3330, 2025

PubMed 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.

PubMed: 40199885
DOI: 10.1038/s41467-025-58690-w

Experimental method

X-RAY DIFFRACTION (2.45 Å)