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*
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104; and
Department of Molecular Biology, DNAX Research Institute, Palo Alto, CA 94303
The capacity of IL-12 to stimulate T and NK cell production of
IFN-
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- in response to infection, whereas administration of
IFN- 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- during
infection, and the ability of splenocytes from infected or uninfected
STAT4-/- mice to produce IFN- 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- 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-. 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- and enhance innate resistance to T.
gondii.
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