Lung epithelial NF-kappaB and Stat1 signaling in response to CD8+ T cell antigen recognition

J Interferon Cytokine Res. 2006 May;26(5):318-27. doi: 10.1089/jir.2006.26.318.

Abstract

CD8+ T cell recognition of viral antigens presented by lung epithelial cells is important in the clearance of respiratory viral infection but may cause considerable injury to the lung. We have shown that a critical event of this type of injury is the activation of target epithelial cells and expression of chemokines by these cells. In this study, epithelial gene expression and transcription factor activation triggered by specific CD8+ T cell antigen recognition was examined in vitro and in vivo. T cell recognition triggers expression profiles of tumor necrosis factor-alpha (TNF-alpha)-dependent and interferon-gamma (IFN-gamma)-dependent genes in epithelial target cells. Consistent with these profiles, transcription factors nuclear factor-kappaB (NF-kappaB) and activator protein-1 (AP-1) were activated in lung epithelial cells of wild-type (WT) mice but not TNF receptor 1 (TNFR1)-deficient mice after CD8+ T cell recognition in vivo. In contrast, Stat1 activation and Stat1-dependent genes, such as IFN regulatory factor-1 (IRF-1) and guanylate-binding protein-2 (GBP-2), were induced to a similar extent in epithelial cells of both WT and TNFR1-deficient mice, indicating that this pathway is insufficient to induce pulmonary immunopathology in the absence of NF-kappaB-dependent transcriptional activation. Antibody neutralization of TNF-alpha abrogated epithelial monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-2 (MIP-2) production in vitro as well as pulmonary immunopathology in vivo, confirming the primary importance of this cytokine in CD8+ T cell-mediated immunopathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cells, Cultured
  • Chemokine CCL2 / genetics
  • Chemokine CXCL2
  • Chemokines / genetics
  • Epithelial Cells / drug effects
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism*
  • Gene Expression Regulation
  • Interferon-gamma / pharmacology
  • Lung / blood supply
  • Lung / drug effects
  • Lung / immunology
  • Lung / metabolism*
  • Mice
  • Mice, Knockout
  • NF-kappa B / metabolism*
  • Oligonucleotide Array Sequence Analysis
  • STAT1 Transcription Factor / metabolism*
  • Signal Transduction
  • Transcription, Genetic / genetics
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Antigens
  • Ccl2 protein, mouse
  • Chemokine CCL2
  • Chemokine CXCL2
  • Chemokines
  • Cxcl2 protein, mouse
  • NF-kappa B
  • STAT1 Transcription Factor
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma