The Journal of Experimental Medicine
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Published online June 30, 2008
doi:10.1084/jem.20080321
The Journal of Experimental Medicine, Vol. 205, No. 7, 1543-1550
The Rockefeller University Press, 0022-1007 $30.00
© 2008 de Beaucoudrey et al.
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BRIEF DEFINITIVE REPORT

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

Ludovic de Beaucoudrey1,2, Anne Puel1,2, Orchidée Filipe-Santos1,2, Aurélie Cobat1,2, Pegah Ghandil1,2, Maya Chrabieh1,2, Jacqueline Feinberg1,2, Horst von Bernuth1,2, Arina Samarina1,2, Lucile Jannière1,2, Claire Fieschi3, Jean-Louis Stéphan4, Catherine Boileau5, Stanislas Lyonnet2,6, Guillaume Jondeau10,11, Valérie Cormier-Daire2,6, Martine Le Merrer2,6, Cyrille Hoarau12,13, Yvon Lebranchu12,13, Olivier Lortholary7, Marie-Olivia Chandesris7, François Tron14,15, Eleonora Gambineri16, Lucia Bianchi16, Carlos Rodriguez-Gallego17, Simona E. Zitnik18, Julia Vasconcelos19, Margarida Guedes20, Artur Bonito Vitor21, Laszlo Marodi22, Helen Chapel23, Brenda Reid24, Chaim Roifman24, David Nadal25, Janine Reichenbach26, Isabel Caragol27, Ben-Zion Garty28, Figen Dogu29, Yildiz Camcioglu30, Sanyie Gülle31, Ozden Sanal32, Alain Fischer2,8,33, Laurent Abel1,2, Birgitta Stockinger34, Capucine Picard1,2,9, and Jean-Laurent Casanova1,2,8

1 Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale (INSERM), 75015 Paris, France
2 University Paris Descartes, Necker Medical School, 75015 Paris, France
3 Immunopathology Unit, Saint-Louis Hospital, Assistance Publique–Hôpitaux de Paris (AP-HP), 75010 Paris, France
4 Department of Pediatrics, Saint-Etienne University Hospital, 42100 Saint-Etienne, France
5 Laboratory of Molecular Genetics, Ambroise Paré Hospital, AP-HP, University Versailles SQY, 92100 Boulogne-Billancourt, France
6 Department of Genetics and U781, INSERM, 7 Department of Infectious Diseases and Tropical Medicine, Necker-Pasteur Infectiology Center, 8 Pediatric Hematology-Immunology Unit, and 9 Study Center of Primary Immunodeficiencies, Necker Hospital, AP-HP, 75015 Paris, France
10 Marfan Multidisciplinary Outpatient Clinic, Bichat Hospital, AP-HP, 75018 Paris, France
11 Paris Diderot University, Bichat Medical School, 75018 Paris, France
12 Dendritic Cells and Grafts, Unité de Formation et de Recherche de Médecine, François Rabelais University, Tours Medical School, 37000 Tours, France
13 Allergy and Immunology Unit, Tours University Hospital, 37000 Tours, France
14 U905, INSERM, Institut Fédératif de Recherche 23, 76100 Rouen, France
15 Medical and Pharmaceutical School, Institute for Biomedical Research, Rouen University Hospital, 76100 Rouen, France
16 Department of Pediatrics, University of Florence, 50132 Florence, Italy
17 Department of Immunology, Hospital Universitario de Gran Canaria Dr. Negrín, 35010 Las Palmas de Gran Canaria, Spain
18 University Children's Hospital, 1000 Ljubljana, Slovenia
19 Department of Immunology and 20 Department of Pediatrics, General Hospital of Santo Antõnio, 4099 Porto, Portugal
21 Department of Pediatrics, Hospital of São João, 4200 Porto, Portugal
22 Department of Infectious and Pediatric Immunology, Medical and Health Science Center, University of Debrecen, 4032 Debrecen, Hungary
23 Department of Immunology, Nuffield Department of Medicine, University of Oxford, OX3 9DU Oxford, England, UK
24 Division of Immunology and Allergy, Department of Pediatrics, Hospital for Sick Children, University of Toronto, M5G 1X8 Toronto, Ontario, Canada
25 Department of Infectious Diseases and 26 Department of Immunology, University Children's Hospital of Zurich, 8032 Zurich, Switzerland
27 Immunology Unit, Vall d'Hebron University Hospital, 08035 Barcelona, Spain
28 Department of Pediatrics, Schneider Children's Medical Center, 49202 Petah Tiqva, Israel
29 Department of Pediatric Immunology and Allergy, Ankara University School of Medicine, 06100 Ankara, Turkey
30 Department of Pediatrics, Infectious Diseases, Clinical Immunology, and Allergy Division, Cerrahpasa Medical School, Istanbul University, 34303 Istanbul, Turkey
31 Department of Pediatrics, Dr. Behçet Uz Children's Research and Training Hospital, 35220 Izmir, Turkey
32 Immunology Division, Hacettepe University Children's Hospital, 06100 Ankara, Turkey
33 Normal and Pathological Development of the Immune System, U768, INSERM, 75015 Paris, France
34 Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, NW7 1AA London, England, UK

CORRESPONDENCE Jean-Laurent Casanova: casanova{at}necker.fr

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.

© 2008 de Beaucoudrey et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jem.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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