Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing

Robert M. Hershberg, Paul E. Framson, Diane H. Cho, Lawrence Y. Lee, Susan Kovats, Jill Beitz, Janice Blum, Gerald T. Nepom

Research output: Contribution to journalArticle

176 Citations (Scopus)

Abstract

Intestinal epithelial cells express a low level of HLA class II molecules constitutively, with elevated levels seen in the setting of mucosal inflammation including inflammatory bowel disease. The ability of intestinal epithelial cells to act as antigen presenting cells for αβ CD4+ T lymphocytes was examined through a molecular analysis of the HLA class II antigen processing pathway. We have shown that intestinal epithelial cells contain abundant constitutive levels of the cathepsin proteases proven to function in HLA class II mediated antigen presentation. Activation of these cells by γ-IFN induced the expression of invariant chain and HLA-DM αβ, thus facilitating the formation of compact, SDS-stable HLA-DR αβ heterodimers. Using HLA-DR-restricted T cells and retrovital mediated gene transfer of HLA-DR alleles into the intestinal epithelial cell lines HT-29 and T84, we demonstrated efficient antigen processing and presentation to CD4+ T lymphocytes in the presence of the proinflammatory cytokine γ-IFN. The class II processing pathway and presentation in the presence of γ-IFN was indistinguishable from that observed with a conventional antigen presenting cell. Antigen processing also occurred in intestinal epithelial cells in the absence of γ-IFN, and in contrast to that seen after stimulation with γ-IFN, required high concentration of antigen and was not inhibited by the protease inhibitor leupeptin. These data suggest the use of two distinct pathways of HLA class II antigen processing in enterocytes with differential immunomodulatory properties in the presence or absence of mucosal inflammation.

Original languageEnglish
Pages (from-to)204-215
Number of pages12
JournalJournal of Clinical Investigation
Volume100
Issue number1
StatePublished - Jul 1 1997

Fingerprint

Histocompatibility Antigens Class II
Antigen Presentation
HLA Antigens
Epithelial Cells
HLA-DR Antigens
Antigen-Presenting Cells
T-Lymphocytes
Inflammation
Cathepsins
Enterocytes
Protease Inhibitors
Inflammatory Bowel Diseases
Peptide Hydrolases
Alleles
Cytokines
Antigens
Cell Line
Genes

Keywords

  • Antigen presentation
  • Human
  • Inflammatory bowel disease
  • Intestinal mucosa
  • T lymphocytes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Hershberg, R. M., Framson, P. E., Cho, D. H., Lee, L. Y., Kovats, S., Beitz, J., ... Nepom, G. T. (1997). Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. Journal of Clinical Investigation, 100(1), 204-215.

Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. / Hershberg, Robert M.; Framson, Paul E.; Cho, Diane H.; Lee, Lawrence Y.; Kovats, Susan; Beitz, Jill; Blum, Janice; Nepom, Gerald T.

In: Journal of Clinical Investigation, Vol. 100, No. 1, 01.07.1997, p. 204-215.

Research output: Contribution to journalArticle

Hershberg, RM, Framson, PE, Cho, DH, Lee, LY, Kovats, S, Beitz, J, Blum, J & Nepom, GT 1997, 'Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing', Journal of Clinical Investigation, vol. 100, no. 1, pp. 204-215.
Hershberg RM, Framson PE, Cho DH, Lee LY, Kovats S, Beitz J et al. Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. Journal of Clinical Investigation. 1997 Jul 1;100(1):204-215.
Hershberg, Robert M. ; Framson, Paul E. ; Cho, Diane H. ; Lee, Lawrence Y. ; Kovats, Susan ; Beitz, Jill ; Blum, Janice ; Nepom, Gerald T. / Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing. In: Journal of Clinical Investigation. 1997 ; Vol. 100, No. 1. pp. 204-215.
@article{1e06fe6ab66f4208a1c274878761fb30,
title = "Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing",
abstract = "Intestinal epithelial cells express a low level of HLA class II molecules constitutively, with elevated levels seen in the setting of mucosal inflammation including inflammatory bowel disease. The ability of intestinal epithelial cells to act as antigen presenting cells for αβ CD4+ T lymphocytes was examined through a molecular analysis of the HLA class II antigen processing pathway. We have shown that intestinal epithelial cells contain abundant constitutive levels of the cathepsin proteases proven to function in HLA class II mediated antigen presentation. Activation of these cells by γ-IFN induced the expression of invariant chain and HLA-DM αβ, thus facilitating the formation of compact, SDS-stable HLA-DR αβ heterodimers. Using HLA-DR-restricted T cells and retrovital mediated gene transfer of HLA-DR alleles into the intestinal epithelial cell lines HT-29 and T84, we demonstrated efficient antigen processing and presentation to CD4+ T lymphocytes in the presence of the proinflammatory cytokine γ-IFN. The class II processing pathway and presentation in the presence of γ-IFN was indistinguishable from that observed with a conventional antigen presenting cell. Antigen processing also occurred in intestinal epithelial cells in the absence of γ-IFN, and in contrast to that seen after stimulation with γ-IFN, required high concentration of antigen and was not inhibited by the protease inhibitor leupeptin. These data suggest the use of two distinct pathways of HLA class II antigen processing in enterocytes with differential immunomodulatory properties in the presence or absence of mucosal inflammation.",
keywords = "Antigen presentation, Human, Inflammatory bowel disease, Intestinal mucosa, T lymphocytes",
author = "Hershberg, {Robert M.} and Framson, {Paul E.} and Cho, {Diane H.} and Lee, {Lawrence Y.} and Susan Kovats and Jill Beitz and Janice Blum and Nepom, {Gerald T.}",
year = "1997",
month = "7",
day = "1",
language = "English",
volume = "100",
pages = "204--215",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "1",

}

TY - JOUR

T1 - Intestinal epithelial cells use two distinct pathways for HLA class II antigen processing

AU - Hershberg, Robert M.

AU - Framson, Paul E.

AU - Cho, Diane H.

AU - Lee, Lawrence Y.

AU - Kovats, Susan

AU - Beitz, Jill

AU - Blum, Janice

AU - Nepom, Gerald T.

PY - 1997/7/1

Y1 - 1997/7/1

N2 - Intestinal epithelial cells express a low level of HLA class II molecules constitutively, with elevated levels seen in the setting of mucosal inflammation including inflammatory bowel disease. The ability of intestinal epithelial cells to act as antigen presenting cells for αβ CD4+ T lymphocytes was examined through a molecular analysis of the HLA class II antigen processing pathway. We have shown that intestinal epithelial cells contain abundant constitutive levels of the cathepsin proteases proven to function in HLA class II mediated antigen presentation. Activation of these cells by γ-IFN induced the expression of invariant chain and HLA-DM αβ, thus facilitating the formation of compact, SDS-stable HLA-DR αβ heterodimers. Using HLA-DR-restricted T cells and retrovital mediated gene transfer of HLA-DR alleles into the intestinal epithelial cell lines HT-29 and T84, we demonstrated efficient antigen processing and presentation to CD4+ T lymphocytes in the presence of the proinflammatory cytokine γ-IFN. The class II processing pathway and presentation in the presence of γ-IFN was indistinguishable from that observed with a conventional antigen presenting cell. Antigen processing also occurred in intestinal epithelial cells in the absence of γ-IFN, and in contrast to that seen after stimulation with γ-IFN, required high concentration of antigen and was not inhibited by the protease inhibitor leupeptin. These data suggest the use of two distinct pathways of HLA class II antigen processing in enterocytes with differential immunomodulatory properties in the presence or absence of mucosal inflammation.

AB - Intestinal epithelial cells express a low level of HLA class II molecules constitutively, with elevated levels seen in the setting of mucosal inflammation including inflammatory bowel disease. The ability of intestinal epithelial cells to act as antigen presenting cells for αβ CD4+ T lymphocytes was examined through a molecular analysis of the HLA class II antigen processing pathway. We have shown that intestinal epithelial cells contain abundant constitutive levels of the cathepsin proteases proven to function in HLA class II mediated antigen presentation. Activation of these cells by γ-IFN induced the expression of invariant chain and HLA-DM αβ, thus facilitating the formation of compact, SDS-stable HLA-DR αβ heterodimers. Using HLA-DR-restricted T cells and retrovital mediated gene transfer of HLA-DR alleles into the intestinal epithelial cell lines HT-29 and T84, we demonstrated efficient antigen processing and presentation to CD4+ T lymphocytes in the presence of the proinflammatory cytokine γ-IFN. The class II processing pathway and presentation in the presence of γ-IFN was indistinguishable from that observed with a conventional antigen presenting cell. Antigen processing also occurred in intestinal epithelial cells in the absence of γ-IFN, and in contrast to that seen after stimulation with γ-IFN, required high concentration of antigen and was not inhibited by the protease inhibitor leupeptin. These data suggest the use of two distinct pathways of HLA class II antigen processing in enterocytes with differential immunomodulatory properties in the presence or absence of mucosal inflammation.

KW - Antigen presentation

KW - Human

KW - Inflammatory bowel disease

KW - Intestinal mucosa

KW - T lymphocytes

UR - http://www.scopus.com/inward/record.url?scp=0030749842&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0030749842&partnerID=8YFLogxK

M3 - Article

C2 - 9202073

AN - SCOPUS:0030749842

VL - 100

SP - 204

EP - 215

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 1

ER -