Toll-Like Receptor 2 Controls the Gamma Interferon Response toFrancisella tularensisby Mouse Liver Lymphocytes

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Abstract
The production of gamma interferon (IFN-γ) is a key step in the protective innate immune response toFrancisella tularensis. Natural killer cells and T cells in the liver are important sources of this cytokine during primaryF. tularensisinfections, and interleukin-12 (IL-12) appears to be an essential coactivating cytokine for hepatic IFN-γ expression. The present study was undertaken to determine whether or not macrophages (Mφ) or dendritic cells (DC) provide coactivating signals for the liver IFN-γ 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 Mφ and DC significantly augmented the IFN-γ response ofF. tularensis-challenged liver lymphocytes in vitro. While both cell types produced IL-12p40 in response toF. tularensischallenge, 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-γ production in response to viableF. tularensisorganisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-γ at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-γ responses toF. tularensisby regulating DC IL-12 production. While Mφ also coinduced hepatic IFN-γ production in response toF. tularensis, they did so in a fashion less dependent on TLR2.