Gliadin activates HLA class I-restricted CD8+ T cells in celiac disease intestinal mucosa and induces the enterocyte apoptosis

Gastroenterology. 2008 Apr;134(4):1017-27. doi: 10.1053/j.gastro.2008.01.008. Epub 2008 Jan 11.

Abstract

Background & aims: The extensive infiltration of CD8(+) T cells in the intestinal mucosa of celiac disease (CD) patients is a hallmark of the disease. We identified a gliadin peptide (pA2) that is selectively recognized by CD8(+) T cells infiltrating intestinal mucosa of HLA-A2(+) CD patients. Herein, we investigated the phenotype, the tissue localization, and the effector mechanism of cells responsive to pA2 by using the organ culture of CD intestinal mucosa. The target of pA2-mediated cytotoxicity was also investigated by using the intestinal epithelial cell lines Caco2 and HT29, A2(+) and A2(-), respectively, as target cells.

Methods: Jejunal biopsy specimens from CD patients were cultured in vitro with pA2, and cellular activation was evaluated by immunohistochemistry and cytofluorimetric analysis. Cytotoxicity of pA2-specific, intestinal CD8(+) T cells was assayed by granzyme-B and interferon-gamma release and by apoptosis of target cells.

Results: pA2 challenge of A2(+) CD mucosa increased the percentage of CD8(+)CD25(+) and of CD80(+) cells in the lamina propria, the former mainly localized beneath the epithelium, as well as the number of terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive cells (TUNEL(+)) in the epithelium. Intraepithelial CD3(+) cells and enterocyte expression of Fas were also increased. CD8(+)CD25(+) and CD8(+)FASL(+) T cells were significantly increased in cell preparations from biopsy specimens cultured with pA2. CD8(+) T-cell lines released both granzyme-B and interferon-gamma following recognition of pA2 when presented by Caco2 and not by HT29.

Conclusions: These data indicate that gliadins contain peptides able to activate, through a TCR/HLA class I interaction, CD8-mediated response in intestinal CD mucosa and to induce the enterocyte apoptosis.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • B7-1 Antigen / immunology
  • Biopsy
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Celiac Disease / immunology*
  • Celiac Disease / metabolism
  • Celiac Disease / pathology
  • Cells, Cultured
  • Enterocytes / pathology*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Flow Cytometry
  • Gliadin / adverse effects
  • Gliadin / metabolism*
  • HLA-A2 Antigen / immunology*
  • Humans
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Jejunum / pathology*
  • Lymphocyte Activation / immunology*
  • Male
  • Middle Aged
  • Organ Culture Techniques
  • fas Receptor / immunology

Substances

  • B7-1 Antigen
  • HLA-A2 Antigen
  • Interleukin-2 Receptor alpha Subunit
  • fas Receptor
  • Gliadin