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Infection and Immunity, April 2009, p. 1492-1501, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01207-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Multiple Mechanisms Contribute to the Robust Rapid Gamma Interferon Response by CD8+ T Cells during Listeria monocytogenes Infection{triangledown}

Elsa N. Bou Ghanem, Denise S. McElroy, and Sarah E. F. D'Orazio*

Department of Microbiology, Immunology, & Molecular Genetics, University of Kentucky, Lexington, Kentucky

Received 29 September 2008/ Returned for modification 13 December 2008/ Accepted 19 January 2009

A subset of CD8+ T cells can rapidly secrete gamma interferon (IFN-{gamma}) in an antigen-independent and interleukin-12 (IL-12)- and IL-18-dependent manner within 16 h of infection with the intracellular bacterial pathogen Listeria monocytogenes. This rapid IFN-{gamma} response is robust enough to be detected directly ex vivo and is not observed following infection with intracellular bacterial pathogens that remain sequestered within host cell vacuoles. We demonstrate here that three distinct pathways can lead to rapid secretion of IFN-{gamma} by CD8+ T cells during L. monocytogenes infection: (i) a direct cytokine-inducing activity encoded by the cholesterol-dependent cytolysin (CDC) listeriolysin O (LLO) acts within the infected cell, (ii) the pore-forming activity of LLO promotes cytosolic localization of bacterial products that trigger cytosol-specific signaling pathways, and (iii) the sustained presence of high concentrations of bacterial products can exogenously trigger cytokine production. Although it has been suggested that CDC protein toxins may act as Toll-like receptor 4 (TLR4) agonists to trigger proinflammatory cytokine secretion, we show in this report that TLR4 signaling is not required to induce a maximal rapid IFN-{gamma} response by CD8+ T cells. The results presented here indicate that multiple mechanisms contribute to the induction of rapid IFN-{gamma} secretion by CD8+ T cells during Listeria infection and that care must be taken when interpreting the results of in vitro assays, since the contribution of each pathway can vary depending on how the assay is performed.

* Corresponding author. Mailing address: Department of Microbiology, Immunology, & Molecular Genetics, University of Kentucky, 800 Rose Street, MS415, Lexington, KY 40536. Phone: (859) 323-8701. Fax: (859) 257-8994. E-mail: sarah.dorazio{at}uky.edu

{triangledown} Published ahead of print on 29 January 2009.

Editor: J. L. Flynn

Infection and Immunity, April 2009, p. 1492-1501, Vol. 77, No. 4
0019-9567/09/$08.00+0     doi:10.1128/IAI.01207-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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