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*
Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati, OH 46267; and
Department of Pediatrics, Louisiana State University Medical Center, Children’s Hospital, New Orleans, LA 70112
Cell-mediated immunity that results in IL-12/IFN-
production is
essential to control infections by intracellular organisms. Studies in
animal models revealed contrasting results in regard to the importance
of CD40-CD40 ligand (CD40L) signaling for induction of a type 1
cytokine response against these pathogens. We demonstrate that
CD40-CD40L interaction in humans is critical for generation of the
IL-12/IFN- immune response against Toxoplasma gondii.
Infection of monocytes with T. gondii resulted in
up-regulation of CD40. CD40-CD40L signaling was required for optimal T
cell production of IFN- in response to T. gondii.
Moreover, patients with hyper IgM (HIGM) syndrome exhibited a defect in
IFN- secretion in response to the parasite and evidence compatible
with impaired in vivo T cell priming after T. gondii
infection. Not only was IL-12 production in response to T.
gondii dependent on CD40-CD40L signaling, but also, patients
with HIGM syndrome exhibited deficient in vitro secretion of this
cytokine in response to the parasite. Finally, in vitro incubation with
agonistic soluble CD40L trimer enhanced T.
gondii-triggered production of IFN- and, through induction
of IL-12 secretion, corrected the defect in IFN- production observed
in HIGM patients. Our results are likely to explain the susceptibility
of patients with HIGM syndrome to infections by opportunistic
pathogens.
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