title: Divergent role for TNF-alpha in IFN-gamma-induced killing of Toxoplasma gondii and Salmonella typhimurium contributes to selective susceptibility of patients with partial IFN-gamma receptor 1 deficiency.
abstract: Patients with defects in IFN-gamma- 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-gamma receptor 1 (IFN-gammaR1) deficiency due to a mutation that results in elevated cell surface expression of a truncated IFN-gammaR1 receptor that lacks the intracellular domain. We show that various effector mechanisms dependent on IFN-gammaR signaling are affected to different extents. Whereas TNF-alpha production was normally up-regulated in response to IFN-gamma, IL-12 production and CD64 up-regulation were strongly reduced, and IFN-gamma-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-alpha as a possible immune compensatory mechanism. IFN-gamma-induced killing of T. gondii appeared to be partially mediated by TNF-alpha, and addition of TNF-alpha could compensate for the abrogated killing of T. gondii in the patient's macrophages. In contrast, IFN-gamma-mediated killing of S. typhimurium appeared to be independent of TNF-alpha. We propose that the divergent role of TNF-alpha in IFN-gamma-induced killing of T. gondii and S. typhimurium may at least partially explain the highly selective susceptibility of patients.
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Riny
authors.initials: R
authors.lastname: Janssen
authors.forename: Annelies
authors.initials: A
authors.lastname: Van Wengen
authors.forename: Els
authors.initials: E
authors.lastname: Verhard
authors.forename: Tjitske
authors.initials: T
authors.lastname: De Boer
authors.forename: Timo
authors.initials: T
authors.lastname: Zomerdijk
authors.forename: Tom H M
authors.initials: TH
authors.lastname: Ottenhoff
authors.forename: Jaap T
authors.initials: JT
authors.lastname: Van Dissel
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology / Q000382:microbiology / Q000469:parasitology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012480:Salmonella Infections / Q000235:genetics / Q000276:immunology; D012486:Salmonella typhimurium / Q000254:growth & development* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014122:Toxoplasma / Q000254:growth & development* / Q000276:immunology*; D014123:Toxoplasmosis / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017452:Receptors, IgG; D017471:Receptors, Interferon; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor