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

J Biol Chem. 2019 Jan 18;294(3):941-952. doi: 10.1074/jbc.RA118.005736. Epub 2018 Nov 19.

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.

Keywords: Celiac Disease; Gluten; Immune response; T-cell; T-cell receptor (TCR); crystal structure; flow cytometry; gluten intolerance; human; immunodominant epitope; major histocompatibility complex (MHC); surface plasmon resonance (SPR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation*
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Glutens / immunology*
  • HLA-DQ Antigens / immunology*
  • Humans
  • Male
  • Peptides / immunology*
  • Receptors, Antigen, T-Cell / immunology*
  • T-Lymphocytes / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • Peptides
  • Receptors, Antigen, T-Cell
  • Glutens

Associated data

  • PDB/6MFG
  • PDB/6MFF