title: Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.
abstract: The IL-12/IFN-gamma axis is crucial for protective immunity to Mycobacterium in humans and mice. Our goal was to analyze the relative contribution of various human blood cell subsets and molecules to the production of, or response to IL-12 and IFN-gamma. We designed an assay for the stimulation of whole blood by live M. bovis Bacillus Calmette-Guerin (BCG) alone, or BCG plus IL-12 or IFN-gamma, measuring IFN-gamma and IL-12 levels. We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-kappaB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4). Patients with deficiencies in IL-12p40, IL-12 receptor beta1 chain (IL-12Rbeta1), IFN-gammaR1, IFN-gammaR2, and STAT-1 were used as internal controls. We showed that monocytes were probably the main producers of IL-12, and that NK and T cells produced similar amounts of IFN-gamma. NEMO and IRAK-4 were found to be important for IL-12 production and subsequent IFN-gamma production, while a lack of CD40L or HLA class II had no major impact on the IL-12/IFN-gamma axis. The stimulation of whole blood by live BCG thus triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.
authors.affiliation: Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker, Paris, France. feinberg@necker.fr
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Feinberg
authors.forename: Claire
authors.initials: C
authors.lastname: Fieschi
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Max
authors.initials: M
authors.lastname: Feinberg
authors.forename: Tony
authors.initials: T
authors.lastname: Leclerc
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Ariane
authors.initials: A
authors.lastname: Chapgier
authors.forename: Orchidée
authors.initials: O
authors.lastname: Filipe-Santos
authors.forename: Cheng-Lung
authors.initials: CL
authors.lastname: Ku
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: Guillemette
authors.initials: G
authors.lastname: Antoni
authors.forename: Ramatoulaye
authors.initials: R
authors.lastname: Baldé
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology / Q000382:microbiology; D002352:Carrier Proteins / Q000097:blood / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051550:I-kappa B Kinase; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D053592:Interleukin-1 Receptor-Associated Kinases; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology* / Q000494:pharmacology; D053762:Interleukin-12 Subunit p40; D007694:Killer Cells, Natural / Q000276:immunology / Q000382:microbiology; D016131:Lymphocyte Subsets / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology* / Q000382:microbiology; D008297:Male; D009000:Monocytes / Q000276:immunology* / Q000382:microbiology; D009163:Mycobacterium bovis / Q000276:immunology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000097:blood / Q000276:immunology*; D021122:Protein Subunits / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000097:blood / Q000235:genetics / Q000276:immunology*
chemical_list: D002352:Carrier Proteins; C491731:IKBKG protein, human; D053762:Interleukin-12 Subunit p40; D021122:Protein Subunits; D018664:Interleukin-12; D007371:Interferon-gamma; D017853:Phosphotransferases (Alcohol Group Acceptor); D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase