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 tissue1,2. 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-γ 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-γ, 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 (TH17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-γt, which is consistent with a crucial role for STAT3 signalling in the generation of TH17 cells7,8,9,10,11,12,13,14. TH17 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 TH17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES.
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This work was supported by the intramural program of the National Institutes of Health.
Author Contributions J.D.M., J.M.B., A.L., B.J.H., K.M.E., Y.K., A.H., H.Z.E., M.L.P. and A.I.A. performed experiments and analysed data. A.F.F., C.S., J.D. and S.M.H. evaluated patients and obtained samples. J.D.M., J.M.B., A.L., J.O’S., S.M.H., W.E.P. and D.C.D. conceived the study, designed experiments, interpreted data and wrote the manuscript.
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Milner, J., Brenchley, J., Laurence, A. et al. Impaired TH17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature 452, 773–776 (2008). https://doi.org/10.1038/nature06764
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