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¹ Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia
² Australian National University Medical School and ³ John Curtin School of Medical Research, Australian National University, Canberra 2600, Australia
⁴ Department of Paediatrics and Child Health, and ⁵ Department of Immunology, The Canberra Hospital, Woden 2606, Australia
⁶ Department of Immunology, Childrens' Hospital at Westmead, and ⁷ Department of Immunology, Institute of Clinical Pathology and Medical Research, Westmead Hospital, Westmead 2145, Australia
⁸ Department of Immunology, Royal Free Hospital & University College London, London WC1E 6BT, England, UK

CORRESPONDENCE Stuart G. Tangye: S.Tangye{at}garvan.org.au OR Matthew C. Cook: matthew.cook{at}anu.edu.au

Hyper–immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4⁺ T cells harboring heterozygous STAT3 mutations to generate interleukin 17–secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.

© 2008 Ma 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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This article has been cited by other articles:

• Tangye, S. G., Cook, M. C., Fulcher, D. A. (2009). Insights into the Role of STAT3 in Human Lymphocyte Differentiation as Revealed by the Hyper-IgE Syndrome. J. Immunol. 182: 21-28 [Abstract] [Full Text]  
• Minegishi, Y., Karasuyama, H. (2008). Defects in Jak-STAT-mediated cytokine signals cause hyper-IgE syndrome: lessons from a primary immunodeficiency. Int Immunol 0: dxn134v1-dxn134 [Abstract] [Full Text]  
• Annunziato, F., Cosmi, L., Liotta, F., Maggi, E., Romagnani, S. (2008). The phenotype of human Th17 cells and their precursors, the cytokines that mediate their differentiation and the role of Th17 cells in inflammation. Int Immunol 20: 1361-1368 [Abstract] [Full Text]  
• Avery, D. T., Ma, C. S., Bryant, V. L., Santner-Nanan, B., Nanan, R., Wong, M., Fulcher, D. A., Cook, M. C., Tangye, S. G. (2008). STAT3 is required for IL-21-induced secretion of IgE from human naive B cells. Blood 112: 1784-1793 [Abstract] [Full Text]  

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