CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-κB-dependent caspase activation

Robert J. Salmond, Richard S. Pitman, Eijiro Jimi, Marco Soriani, Timothy R. Hirst, Sankar Ghosh, Mercedes Rincón, Neil A. Williams

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

The B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule capable of treating and preventing autoimmune disease. These properties result from its ability to bind to glycolipid receptors, principally GM1 ganglioside, and modulate immune cell function. EtxB receptor binding causes B cell activation, modulates monocyte cytokine secretion and triggers apoptosis of CD8+ T cells. These wide-ranging effects suggest that B subunit receptor interaction triggers signaling events affecting cellular differentiation. We have investigated the processes by which EtxB induces CD8+ T cell apoptosis. We show that receptor interaction by EtxB activates caspase-3 in CD8+ but not in CD4+ T cells. Inhibition of caspase-3 blocks the apoptotic process. EtxB induces the activation of NF-κB in both CD8+ and CD4+ T cells. The findings that (i) SN50, a peptide inhibitor of NF-κB nuclear translocation, prevents caspase-3 activation and subsequent apoptosis, and (ii) CD8+CD4- thymocytes from transgenic mice expressing a dominant-negative form of the IκBα protein were markedly less susceptible to EtxB-induced apoptosis than cells from wild-type mice, indicate that NF-κB is important in the induction of the apoptotic pathway. Further investigations revealed that while caspase-8 activity is detected concomitant to caspase-3, caspase-9 activation, following mitochondrial cytochrome c release, is detectable later on. These observations are consistent with death receptor-mediated signaling, however, experiments using lpr/lpr and p55 TNFR -/- mice rule out the involvement of Fas and the p55 TNF receptor, respectively. The data therefore indicate that EtxB-mediated apoptosis occurs via a novel pathway involving NF-κB.

Original languageEnglish
Pages (from-to)1737-1747
Number of pages11
JournalEuropean Journal of Immunology
Volume32
Issue number6
DOIs
Publication statusPublished - Jul 4 2002

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Enterotoxins
Caspases
Hot Temperature
Caspase 3
Apoptosis
Escherichia coli
T-Lymphocytes
G(M1) Ganglioside
Death Domain Receptors
Caspase 9
Caspase 8
Thymocytes
Cytochromes c
Transgenic Mice
Autoimmune Diseases
Monocytes
B-Lymphocytes
Cytokines
Proteins

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-κB-dependent caspase activation. / Salmond, Robert J.; Pitman, Richard S.; Jimi, Eijiro; Soriani, Marco; Hirst, Timothy R.; Ghosh, Sankar; Rincón, Mercedes; Williams, Neil A.

In: European Journal of Immunology, Vol. 32, No. 6, 04.07.2002, p. 1737-1747.

Research output: Contribution to journalArticle

Salmond, Robert J. ; Pitman, Richard S. ; Jimi, Eijiro ; Soriani, Marco ; Hirst, Timothy R. ; Ghosh, Sankar ; Rincón, Mercedes ; Williams, Neil A. / CD8+ T cell apoptosis induced by Escherichia coli heat-labile enterotoxin B subunit occurs via a novel pathway involving NF-κB-dependent caspase activation. In: European Journal of Immunology. 2002 ; Vol. 32, No. 6. pp. 1737-1747.
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