Toll-like receptor 2 controls the gamma interferon response to Francisella tularensis by mouse liver lymphocytes.
The production of gamma interferon (IFN-gamma) 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-gamma expression. The present study was undertaken to determine whether or not macrophages (Mphi) or dendritic cells (DC) provide coactivating signals for the liver IFN-gamma 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 Mphi and DC significantly augmented the IFN-gamma 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-gamma production in response to viable F. tularensis organisms. Conversely, liver lymphocytes from TLR2-deficient mice cocultured with wild-type accessory cells produced IFN-gamma at levels comparable to those for wild-type hepatic lymphocytes. These findings indicate that TLR2 controls hepatic lymphocyte IFN-gamma responses to F. tularensis by regulating DC IL-12 production. While Mphi also coinduced hepatic IFN-gamma production in response to F. tularensis, they did so in a fashion less dependent on TLR2.
Hong
Kee-Jong
KJ
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
Wickstrum
Jason R
JR
Yeh
Hung-Wen
HW
Parmely
Michael J
MJ
D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology; D053765:Interleukin-12 Subunit p35 / Q000172:deficiency; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000276:immunology*