A molecular basis for the T cell response in HLA-DQ2.2 mediated celiac disease

Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):3063-3073. doi: 10.1073/pnas.1914308117. Epub 2020 Jan 23.


The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.

Keywords: T cell receptor; X-ray crystallography; celiac disease; human leukocyte antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4-Positive T-Lymphocytes / chemistry
  • CD4-Positive T-Lymphocytes / metabolism
  • Celiac Disease* / genetics
  • Celiac Disease* / immunology
  • Celiac Disease* / metabolism
  • Cell Line
  • Crystallography, X-Ray
  • Epitopes, T-Lymphocyte / chemistry
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / metabolism
  • Glutens / chemistry
  • Glutens / immunology
  • Glutens / metabolism
  • HLA-DQ Antigens* / chemistry
  • HLA-DQ Antigens* / genetics
  • HLA-DQ Antigens* / metabolism
  • Humans
  • Models, Molecular
  • Protein Binding
  • Receptors, Antigen, T-Cell* / chemistry
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / metabolism


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

Associated data

  • PDB/6PX6
  • PDB/6PY2