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

Journal article

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.

Authors: Dahal-Koirala, S; Ciacchi, L; Petersen, J; Risnes, LF; Neumann, RS

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: Journal of Biological Chemistry
• Volume: 294
• Issue: 3
• Pages: 941-952
• Publication date: 2018-11-19
• Acceptance date: 2018-11-05
• DOI: 10.1074/jbc.ra118.005736
• EISSN: 1083-351X
• ISSN: 0021-9258
• Language: English
• Keywords: T-cell; T-cell receptor (TCR); major histocompatibility complex (MHC); crystal structure; surface plasmon resonance (SPR); flow cytometry; celiac disease; gluten; gluten intolerance; immune response; immunodominant epitope