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Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

2008; Rockefeller University Press; Volume: 205; Issue: 7 Linguagem: Inglês

10.1084/jem.20080321

1540-9538

Ludovic de Beaucoudrey, Anne Puel, Orchidée Filipe‐Santos, Aurélie Cobat, Pegah Ghandil, Maya Chrabieh, Jacqueline Feinberg, Horst von Bernuth, Arina Samarina, Lucile Jannière, Claire Fieschi, Jean-Louis Stéphan, Cathérine Boileau, Stanislas Lyonnet, Guillaume Jondeau, Valérie Cormier‐Daire, Martine Le Merrer, C. Hoarau, Yvon Lebranchu, Olivier Lortholary, Marie‐Olivia Chandesris, François Tron, Eleonora Gambineri, Lucia Bianchi, Carlos Rodríguez‐Gallego, Simona Eva Zitnik, Júlia Vasconcelos, Margarida Guedes, Artur Bonito Vítor, László Maródi, Helen Chapel, Brenda Reid, Chaim M. Roifman, David Nadal, Janine Reichenbach, Isabel Caragol, Ben‐Zion Garty, Figen Doğu, Yıldız Çamcıoğlu, Sanyie Gülle, Özden Sanal, Alain Fischer, Laurent Abel, Brigitta Stockinger, Capucine Pïcard, Jean‐Laurent Casanova,

Autoimmune and Inflammatory Disorders

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) β, 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-12Rβ1– 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.