Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
de Beaucoudrey
Ludovic
L
Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France. casanova@necker.fr
Puel
Anne
A
Filipe-Santos
Orchidée
O
Cobat
Aurélie
A
Ghandil
Pegah
P
Chrabieh
Maya
M
Feinberg
Jacqueline
J
von Bernuth
Horst
H
Samarina
Arina
A
Jannière
Lucile
L
Fieschi
Claire
C
Stéphan
Jean-Louis
JL
Boileau
Catherine
C
Lyonnet
Stanislas
S
Jondeau
Guillaume
G
Cormier-Daire
Valérie
V
Le Merrer
Martine
M
Hoarau
Cyrille
C
Lebranchu
Yvon
Y
Lortholary
Olivier
O
Chandesris
Marie-Olivia
MO
Tron
François
F
Gambineri
Eleonora
E
Bianchi
Lucia
L
Rodriguez-Gallego
Carlos
C
Zitnik
Simona E
SE
Vasconcelos
Julia
J
Guedes
Margarida
M
Vitor
Artur Bonito
AB
Marodi
Laszlo
L
Chapel
Helen
H
Reid
Brenda
B
Roifman
Chaim
C
Nadal
David
D
Reichenbach
Janine
J
Caragol
Isabel
I
Garty
Ben-Zion
BZ
Dogu
Figen
F
Camcioglu
Yildiz
Y
Gülle
Sanyie
S
Sanal
Ozden
O
Fischer
Alain
A
Abel
Laurent
L
Stockinger
Birgitta
B
Picard
Capucine
C
Casanova
Jean-Laurent
JL
D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008297:Male; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D040641:Quantitative Trait Loci / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000276:immunology*; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D016207:Cytokines; C508438:IL12RB1 protein, human; D020381:Interleukin-17; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D053707:Receptors, Interleukin-12; D018125:Receptors, Transforming Growth Factor beta; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human