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in IFN-
-Induced Killing of Toxoplasma gondii and Salmonella typhimurium Contributes to Selective Susceptibility of Patients with Partial IFN- Receptor 1 Deficiency1
Departments of
* Infectious Diseases and
Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
Patients with defects in IFN-
- or IL-12-mediated
immunity are susceptible to infections with Salmonella
and non-tuberculous mycobacteria, but rarely suffer from infections
with other intracellular pathogens such as Toxoplasma
gondii. Here we describe macrophage and T cell function in
eight individuals with partial IFN- receptor 1 (IFN-R1)
deficiency due to a mutation that results in elevated cell surface
expression of a truncated IFN-R1 receptor that lacks the
intracellular domain. We show that various effector mechanisms
dependent on IFN-R signaling are affected to different extents.
Whereas TNF-
production was normally up-regulated in response to
IFN-, IL-12 production and CD64 up-regulation were strongly reduced,
and IFN--mediated killing of the intracellular pathogens
Salmonella typhimurium and T. gondii was
completely abrogated in patient’s macrophages. Since these patients
suffer selectively from infections with non-tuberculous mycobacteria
and Salmonella, but not T. gondii,
despite sero-immunity in six of eight patients, which indicates
previous contact with this pathogen, we next studied the role of
TNF- as a possible immune compensatory mechanism. IFN--induced
killing of T. gondii appeared to be partially mediated
by TNF-, and addition of TNF- could compensate for the abrogated
killing of T. gondii in the patient’s macrophages. In
contrast, IFN--mediated killing of S. typhimurium
appeared to be independent of TNF-. We propose that the divergent
role of TNF- in IFN--induced killing of T. gondii
and S. typhimurium may at least partially explain the
highly selective susceptibility of patients.
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