title: Coactivating signals for the hepatic lymphocyte gamma interferon response to Francisella tularensis.
abstract: The facultative intracellular bacterium Francisella tularensis is capable of causing systemic infections in various hosts, including mice and humans. The liver is a major secondary site of F. tularensis infection, but hepatic immune responses to the pathogen remain poorly defined. Immune protection against the pathogen is thought to depend on the cytokine gamma interferon (IFN-gamma), but the cellular basis for this response has not been characterized. Here we report that natural killer cells from the livers of naïve uninfected mice produced IFN-gamma when challenged with live bacteria in vitro and that the responses were greatly increased by coactivation of the cells with either recombinant interleukin-12 (IL-12) or IL-18. Moreover, the two cytokines had strong synergistic effects on IFN-gamma induction. Neutralizing antibodies to either IL-12 or IL-18 inhibited IFN-gamma production in vitro, and mice deficient in the p35 subunit of IL-12 failed to show IFN-gamma responses to bacterial challenge either in vitro or in vivo. Clinical isolates of highly virulent type A Francisella tularensis subsp. tularensis organisms were comparable to the live attenuated vaccine strain of Francisella tularensis subsp. holarctica in their ability to induce IL-12 and IFN-gamma expression. These findings demonstrate that cells capable of mounting IFN-gamma responses to F. tularensis are resident within the livers of uninfected mice and depend on coactivation by IL-12 and IL-18 for optimum responses.
authors.affiliation: Department of Microbiology, Molecular Genetics, and Immunology, University of Kansas Medical Center, 3901 Rainbow Blvd., Kansas City, KS 66160, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Wickstrum
authors.forename: Kee-Jong
authors.initials: KJ
authors.lastname: Hong
authors.forename: Sirosh
authors.initials: S
authors.lastname: Bokhari
authors.forename: Natalie
authors.initials: N
authors.lastname: Reed
authors.forename: Nicholas
authors.initials: N
authors.lastname: McWilliams
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Horvat
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Parmely
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D005260:Female; D005604:Francisella tularensis / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis*; D008099:Liver / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D007371:Interferon-gamma