HLA-DQ2 and -DQ8 Signatures of Gluten T Cell Epitopes in Celiac Disease

J Clin Invest. 2006 Aug;116(8):2226-36. doi: 10.1172/JCI27620. Epub 2006 Jul 27.

Abstract

Celiac disease is associated with HLA-DQ2 and, to a lesser extent, HLA-DQ8. Type 1 diabetes is associated with the same DQ molecules in the opposite order and with possible involvement of trans-encoded DQ heterodimers. T cells that are reactive with gluten peptides deamidated by transglutaminase 2 and invariably restricted by DQ2 or DQ8 can be isolated from celiac lesions. We used intestinal T cells from celiac patients to map DQ2 and DQ8 epitopes within 2 representative gluten proteins, alpha-gliadin AJ133612 and gamma-gliadin M36999. For alpha-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of 2 separate regions. For gamma-gliadin, DQ2- and DQ8-restricted T cells recognized deamidated peptides of the same region. Some gamma-gliadin peptides were recognized by T cells in the context of DQ2 or DQ8 when bound in exactly the same registers, but with different requirements for deamidation; deamidation at peptide position 4 (P4) was important for DQ2-restricted T cells, whereas deamidation at P1 and/or P9 was important for DQ8-restricted T cells. Peptides combining the DQ2 and DQ8 signatures could be presented by DQ2, DQ8, and trans-encoded DQ heterodimers. Our findings shed light on the basis for the HLA associations in celiac disease and type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Celiac Disease / immunology*
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 1 / immunology
  • Dimerization
  • Epitopes / chemistry
  • Gliadin / chemistry
  • Gliadin / genetics
  • HLA Antigens / genetics
  • HLA Antigens / immunology
  • HLA-DQ Antigens / chemistry
  • HLA-DQ Antigens / genetics*
  • Humans
  • Immunity, Mucosal
  • Molecular Sequence Data
  • Peptide Fragments / chemistry
  • T-Lymphocytes / immunology*

Substances

  • Epitopes
  • HLA Antigens
  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • Peptide Fragments
  • Gliadin