title: Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
abstract: 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.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France. casanova@necker.fr
authors.forename: Ludovic
authors.initials: L
authors.lastname: de Beaucoudrey
authors.forename: Anne
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authors.lastname: Puel
authors.forename: Orchidée
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authors.lastname: Filipe-Santos
authors.forename: Aurélie
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authors.forename: Pegah
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authors.lastname: Ghandil
authors.forename: Maya
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authors.forename: Jacqueline
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authors.lastname: Feinberg
authors.forename: Horst
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authors.forename: Lucile
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authors.lastname: Jannière
authors.forename: Claire
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authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Stéphan
authors.forename: Catherine
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authors.lastname: Lyonnet
authors.forename: Guillaume
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authors.forename: Valérie
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authors.forename: Martine
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authors.forename: Cyrille
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authors.forename: Yvon
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authors.forename: Marie-Olivia
authors.initials: MO
authors.lastname: Chandesris
authors.forename: François
authors.initials: F
authors.lastname: Tron
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gambineri
authors.forename: Lucia
authors.initials: L
authors.lastname: Bianchi
authors.forename: Carlos
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authors.lastname: Rodriguez-Gallego
authors.forename: Simona E
authors.initials: SE
authors.lastname: Zitnik
authors.forename: Julia
authors.initials: J
authors.lastname: Vasconcelos
authors.forename: Margarida
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authors.lastname: Guedes
authors.forename: Artur Bonito
authors.initials: AB
authors.lastname: Vitor
authors.forename: Laszlo
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authors.lastname: Marodi
authors.forename: Helen
authors.initials: H
authors.lastname: Chapel
authors.forename: Brenda
authors.initials: B
authors.lastname: Reid
authors.forename: Chaim
authors.initials: C
authors.lastname: Roifman
authors.forename: David
authors.initials: D
authors.lastname: Nadal
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
authors.forename: Isabel
authors.initials: I
authors.lastname: Caragol
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Garty
authors.forename: Figen
authors.initials: F
authors.lastname: Dogu
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioglu
authors.forename: Sanyie
authors.initials: S
authors.lastname: Gülle
authors.forename: Ozden
authors.initials: O
authors.lastname: Sanal
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Birgitta
authors.initials: B
authors.lastname: Stockinger
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
mesh_terms: 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*
chemical_list: 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