1. Laboratory of Immunology,
2. Human Immunology Section, Vaccine Research Center, and,
3. Lymphocyte Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,
4. Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
5. Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
6. These authors contributed equally to this work.
7. Present address: Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

Correspondence to: Daniel C. Douek² Correspondence and requests for materials should be addressed to D.C.D. (Email: ddouek@nih.gov).

The autosomal dominant hyper-IgE syndrome (HIES, 'Job's syndrome') is characterized by recurrent and often severe pulmonary infections, pneumatoceles, eczema, staphylococcal abscesses, mucocutaneous candidiasis, and abnormalities of bone and connective tissue^{1, 2}. Mutations presumed to underlie HIES have recently been identified in stat3, the gene encoding STAT3 (signal transducer and activator of transcription 3) (refs 3, 4). Although impaired production of interferon- and tumour-necrosis factor by T cells⁵, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens⁶ have variably been described, specific immunological abnormalities that can explain the unique susceptibility to particular infections seen in HIES have not yet been defined. Here we show that interleukin (IL)-17 production by T cells is absent in HIES individuals. We observed that ex vivo T cells from subjects with HIES failed to produce IL-17, but not IL-2, tumour-necrosis factor or interferon-, on mitogenic stimulation with staphylococcal enterotoxin B or on antigenic stimulation with Candida albicans or streptokinase. Purified naive T cells were unable to differentiate into IL-17-producing (T_H17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-t, which is consistent with a crucial role for STAT3 signalling in the generation of T_H17 cells^{7, 8, 9, 10, 11, 12, 13, 14}. T_H17 cells have emerged as an important subset of helper T cells¹⁵ that are believed to be critical in the clearance of fungal¹⁶ and extracellular bacterial¹⁷ infections. Thus, our data suggest that the inability to produce T_H17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES.

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