Transglutaminase 2 affinity and enzyme-substrate intermediate stability as determining factors for T-cell responses to gluten peptides in celiac disease

Eur J Immunol. 2022 Sep;52(9):1474-1481. doi: 10.1002/eji.202249862. Epub 2022 Jul 13.


The adaptive immune response of celiac disease (CeD) involves presentation of gluten peptides to CD4+ T cells by transglutaminase 2 (TG2) specific B cells. This B-cell/T-cell crosstalk is facilitated by involvement of TG2:gluten peptide complexes that act principally in the form of enzyme-substrate intermediates. Here, we have addressed how gluten peptide affinity and complex stability in the presence of secondary substrates affect the uptake of TG2:gluten peptide complexes by TG2-specific B cells and the activation of gluten-specific T cells. We studied affinity of various gluten peptides for TG2 by biochemical assay, and monitored uptake of gluten peptides by TG2-specific B cells by flow cytometry. Crosstalk between TG2-specific B cells and gluten-specific T cells was assayed with transfectants expressing antigen receptors derived from CeD patients. We found that gluten peptides with high TG2 affinity showed better uptake by TG2-specific B cells. Uptake by B cells, and subsequent activation of T cells, was negatively affected by polyamines acting as secondary TG2 substrates. These results show that affinity between gluten peptide and TG2 governs the selection of T-cell epitopes via enhanced uptake of TG2:gluten complexes by TG2-specific B cells, and that exogenous polyamines can influence the CeD immune responses by disrupting TG2:gluten complexes.

Keywords: B cells; T cells; autoimmunity; celiac disease; transglutaminase 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Celiac Disease*
  • GTP-Binding Proteins / metabolism
  • Glutens*
  • Humans
  • Peptides / metabolism
  • Polyamines
  • Protein Glutamine gamma Glutamyltransferase 2
  • T-Lymphocytes
  • Transglutaminases


  • Peptides
  • Polyamines
  • Glutens
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins