Journal
JOURNAL OF IMMUNOLOGY
Volume 165, Issue 5, Pages 2619-2627Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.165.5.2619
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- NIAID NIH HHS [AI42334-01] Funding Source: Medline
- NIDDK NIH HHS [P30 DK 50306] Funding Source: Medline
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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.
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