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Infection and Immunity, October 2004, p. 5850-5857, Vol. 72, No. 10
0019-9567/04/$08.00+0     DOI: 10.1128/IAI.72.10.5850-5857.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The B Subunit of Escherichia coli Heat-Labile Enterotoxin Induces Both Caspase-Dependent and -Independent Cell Death Pathways in CD8⁺ T Cells

Robert J. Salmond, Rachel Williams, Timothy R. Hirst, and Neil A. Williams^*

Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom

Received 16 February 2004/ Returned for modification 30 March 2004/ Accepted 25 June 2004

The nontoxic B subunit of Escherichia coli heat-labile enterotoxin (EtxB) is a potent immunomodulatory molecule that acts both as an adjuvant and to stimulate immune deviation processes, resulting in the suppression of Th1-associated inflammatory responses. The ability of EtxB to alter immune reactivity is dependent on its ability to modulate immune cell function through binding to cell surface molecules, the principal receptor of which is the ubiquitous G_M1-ganglioside. EtxB activates B cells and antigen-presenting cells and induces the selective apoptosis of murine CD8⁺ T cells. We postulated that these effects are mediated by the induction of intracellular signaling pathways following EtxB-receptor interaction. We have previously shown that CD8⁺ T-cell apoptosis induced by EtxB results from the activation of the transcription factor NF-B and caspases. Here we report that while caspase activity is required for apoptosis, additional features of cell death are caspase independent. EtxB induces a rapid loss of mitochondrial membrane potential and cell viability that are unaffected by caspase inhibitors. In addition, our data suggest that these processes are independent of the activity of Bax and Bcl-2 but are mediated by nitric oxide synthase.

Editor: J. D. Clements

Present address: Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham, Cambridge CB2 4AT, United Kingdom.

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