Discriminative T-cell receptor recognition of highly homologous HLA-DQ2–bound gluten epitopes

Dahal-Koirala, Shiva, Ciacchi, Laura, Petersen, Jan, Risnes, Louise Fremgaard, Neumann, Ralf Stefan, Christophersen, Asbjørn, Lundin, Knut E. A., Reid, Hugh H., Qiao, Shuo-Wang, Rossjohn, Jamie ORCID: https://orcid.org/0000-0002-2020-7522 and Sollid, Ludvig M. 2019. Discriminative T-cell receptor recognition of highly homologous HLA-DQ2–bound gluten epitopes. Journal of Biological Chemistry 294 (3) , pp. 941-952. 10.1074/jbc.RA118.005736

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	American Society for Biochemistry and Molecular Biology
ISSN:	0021-9258
Date of First Compliant Deposit:	16 April 2019
Date of Acceptance:	5 November 2018
Last Modified:	01 Dec 2024 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/119800

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