Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.
de Beaucoudrey, Ludovic 1,2; Puel, Anne 1,2; Filipe-Santos, Orchidee 1,2; Cobat, Aurelie 1,2; Ghandil, Pegah 1,2; Chrabieh, Maya 1,2; Feinberg, Jacqueline 1,2; von Bernuth, Horst 1,2; Samarina, Arina 1,2; Janniere, Lucile 1,2; Fieschi, Claire 3; Stephan, Jean-Louis 4; Boileau, Catherine 5; Lyonnet, Stanislas 2,6; Jondeau, Guillaume 10,11; Cormier-Daire, Valerie 2,6; Le Merrer, Martine 2,6; Hoarau, Cyrille 12,13; Lebranchu, Yvon 12,13; Lortholary, Olivier 7; Chandesris, Marie-Olivia 7; Tron, Francois 14,15; Gambineri, Eleonora 16; Bianchi, Lucia 16; Rodriguez-Gallego, Carlos 17; Zitnik, Simona E. 18; Vasconcelos, Julia 19; Guedes, Margarida 20; Vitor, Artur Bonito 21; Marodi, Laszlo 22; Chapel, Helen 23; Reid, Brenda 24; Roifman, Chaim 24; Nadal, David 25; Reichenbach, Janine 26; Caragol, Isabel 27; Garty, Ben-Zion 28; Dogu, Figen 29; Camcioglu, Yildiz 30; Gulle, Sanyie 31; Sanal, Ozden 32; Fischer, Alain 2,8,33; Abel, Laurent 1,2; Stockinger, Birgitta 34; Picard, Capucine 1,2,9; Casanova, Jean-Laurent 1,2,8
[Report]
Journal of Experimental Medicine.
205(7):1543-1550, July 7, 2008.
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: 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-12R[beta]1- 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.
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