Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells
de Beaucoudrey L., Puel A., Filipe-Santos O., Cobat A., Ghandil P., Chrabieh M., Feinberg J., von Bernuth H., Samarina A., Jannière L., Fieschi C., Stéphan J-L., Boileau C., Lyonnet S., Jondeau G., Cormier-Daire V., Le Merrer M., Hoarau C., Lebranchu Y., Lortholary O., Chandesris M-O., Tron F., Gambineri E., Bianchi L., Rodriguez-Gallego C., Zitnik SE., Vasconcelos J., Guedes M., Vitor AB., Marodi L., Chapel H., Reid B., Roifman C., Nadal D., Reichenbach J., Caragol I., Garty B-Z., Dogu F., Camcioglu Y., Gülle S., Sanal O., Fischer A., Abel L., Stockinger B., Picard C., Casanova J-L.
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.