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.
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.
Feinberg
Jacqueline
J
Laboratoire de Génétique Humaine des Maladies Infectieuses, Université de Paris René Descartes INSERM U550, Faculté de Médecine Necker, Paris, France. feinberg@necker.fr
Fieschi
Claire
C
Doffinger
Rainer
R
Feinberg
Max
M
Leclerc
Tony
T
Boisson-Dupuis
Stéphanie
S
Picard
Capucine
C
Bustamante
Jacinta
J
Chapgier
Ariane
A
Filipe-Santos
Orchidée
O
Ku
Cheng-Lung
CL
de Beaucoudrey
Ludovic
L
Reichenbach
Janine
J
Antoni
Guillemette
G
Baldé
Ramatoulaye
R
Alcaïs
Alexandre
A
Casanova
Jean-Laurent
JL
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*
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