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Toll-Like Receptor 2 Controls the Gamma Interferon Response to Francisella tularensis by Mouse Liver Lymphocytes

Kee-Jong Hong,^1, Jason R. Wickstrum,^1, Hung-Wen Yeh,² and Michael J. Parmely^1*

Department of Microbiology, Molecular Genetics and Immunology,¹ Department of Biostatistics, University of Kansas Medical Center, Kansas City, Kansas 66160²

Received 18 April 2007/ Returned for modification 19 June 2007/ Accepted 25 August 2007

The production of gamma interferon (IFN-) is a key step in the protective innate immune response to Francisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primary F. tularensis infections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN- expression. The present study was undertaken to determine whether or not macrophages (M) or dendritic cells (DC) provide coactivating signals for the liver IFN- response in vitro, whether IL-12 mediates these effects, and whether Toll-like receptor (TLR) signaling is essential to induce this costimulatory activity. Both bone marrow-derived M and DC significantly augmented the IFN- response of F. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response to F. tularensis challenge, only DC secreted large quantities of IL-12p70. DC from both IL-12p35-deficient and TLR2-deficient mice failed to produce IL-12p70 and did not costimulate liver lymphocytes for IFN- production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN- at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN- responses to F. tularensis by regulating DC IL-12 production. While M also coinduced hepatic IFN- production in response to F. tularensis, they did so in a fashion less dependent on TLR2.

Published ahead of print on 4 September 2007.

Editor: J. L. Flynn

These authors contributed equally to this study.

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