title: Identification of STAT4-dependent and independent mechanisms of resistance to Toxoplasma gondii.
abstract: The capacity of IL-12 to stimulate T and NK cell production of IFN-gamma is required for resistance to Toxoplasma gondii. To identify the transcription factors involved in this mechanism of resistance, mice deficient in STAT4, a protein involved in IL-12 signaling, were infected with T. gondii and their immune responses were analyzed. STAT4-/- mice were unable to control parasite replication and died during the acute phase of infection, whereas wild-type mice controlled parasite replication and survived this challenge. The susceptibility of STAT4-/- mice to toxoplasmosis correlated with a defect in their ability to produce IFN-gamma in response to infection, whereas administration of IFN-gamma to these mice inhibited parasite replication and delayed time to death. Interestingly, analysis of infected STAT4-/- mice revealed that these mice did produce low levels of IFN-gamma during infection, and the ability of splenocytes from infected or uninfected STAT4-/- mice to produce IFN-gamma was enhanced by the addition of IL-2 plus IL-18. Moreover, administration of IL-2 plus IL-18 to STAT4-/- mice resulted in elevated serum levels of IFN-gamma associated with a decreased parasite burden and delayed time to death. In vivo depletion studies demonstrated that the ability of IL-2 plus IL-18 to mediate STAT4-independent resistance to T. gondii is dependent on NK cell production of IFN-gamma. Together, these studies identify STAT4 as an important transcription factor required for development of the innate NK and adaptive T cell responses necessary for resistance to T. gondii. However, other signaling pathways can be used to bypass STAT4-dependent production of IFN-gamma and enhance innate resistance to T. gondii.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: G
authors.initials: G
authors.lastname: Cai
authors.forename: T
authors.initials: T
authors.lastname: Radzanowski
authors.forename: E N
authors.initials: EN
authors.lastname: Villegas
authors.forename: R
authors.initials: R
authors.lastname: Kastelein
authors.forename: C A
authors.initials: CA
authors.lastname: Hunter
mesh_terms: D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D002460:Cell Line; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004357:Drug Synergism; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007371:Interferon-gamma / Q000096:biosynthesis / Q000097:blood; D020382:Interleukin-18 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D050797:STAT4 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D014122:Toxoplasma / Q000276:immunology*; D014124:Toxoplasmosis, Animal / Q000209:etiology / Q000235:genetics / Q000276:immunology; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
chemical_list: D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D020382:Interleukin-18; D007376:Interleukin-2; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma