6MFF

HLA-DQ2-glia-omega1

Summary for 6MFF

• Entry DOI: 10.2210/pdb6mff/pdb
• Descriptor: HLA class II histocompatibility antigen, DQ alpha 1 chain, MHC class II HLA-DQ-beta-1 - DQ2-glia-omega1 chimeric protein, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: immune complex, celiac disease, gliadin epitope, tcr cross-reactivity, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 47657.97

Authors

Petersen, J.,Ciacchi, L.,Rossjohn, J. (deposition date: 2018-09-10, release date: 2018-11-21, Last modification date: 2024-10-23)

Primary citation

Dahal-Koirala, S.,Ciacchi, L.,Petersen, J.,Risnes, L.F.,Neumann, R.S.,Christophersen, A.,Lundin, K.E.A.,Reid, H.H.,Qiao, S.W.,Rossjohn, J.,Sollid, L.M.
Discriminative T-cell receptor recognition of highly homologous HLA-DQ2-bound gluten epitopes.
J. Biol. Chem., 294:941-952, 2019

PubMed Abstract: Celiac disease (CeD) provides an opportunity to study the specificity underlying human T-cell responses to an array of similar epitopes presented by the same human leukocyte antigen II (HLA-II) molecule. Here, we investigated T-cell responses to the two immunodominant and highly homologous HLA-DQ2.5-restricted gluten epitopes, DQ2.5-glia-α1a (PFPQPELPY) and DQ2.5-glia-ω1 (PFPQPEQPF). Using HLA-DQ2.5-DQ2.5-glia-α1a and HLA-DQ2.5-DQ2.5-glia-ω1 tetramers and single-cell αβ T-cell receptor (TCR) sequencing, we observed that despite similarity in biased variable-gene usage in the TCR repertoire responding to these nearly identical peptide-HLA-II complexes, most of the T cells are specific for either of the two epitopes. To understand the molecular basis of this exquisite fine specificity, we undertook Ala substitution assays revealing that the p7 residue (Leu/Gln) is critical for specific epitope recognition by both DQ2.5-glia-α1a- and DQ2.5-glia-ω1-reactive T-cell clones. We determined high-resolution binary crystal structures of HLA-DQ2.5 bound to DQ2.5-glia-α1a (2.0 Å) and DQ2.5-glia-ω1 (2.6 Å). These structures disclosed that differences around the p7 residue subtly alter the neighboring substructure and electrostatic properties of the HLA-DQ2.5-peptide complex, providing the fine specificity underlying the responses against these two highly homologous gluten epitopes. This study underscores the ability of TCRs to recognize subtle differences in the peptide-HLA-II landscape in a human disease setting.

PubMed: 30455354
DOI: 10.1074/jbc.RA118.005736

Experimental method

X-RAY DIFFRACTION (2.6 Å)