title: Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.
abstract: 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. 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-gamma and tumour-necrosis factor by T cells, diminished memory T-cell populations, decreased delayed-type-hypersensitivity responses and decreased in vitro lymphoproliferation in response to specific antigens 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-gamma, 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(H)17) T helper cells in vitro and had lower expression of retinoid-related orphan receptor (ROR)-gammat, which is consistent with a crucial role for STAT3 signalling in the generation of T(H)17 cells. T(H)17 cells have emerged as an important subset of helper T cells that are believed to be critical in the clearance of fungal and extracellular bacterial infections. Thus, our data suggest that the inability to produce T(H)17 cells is a mechanism underlying the susceptibility to the recurrent infections commonly seen in HIES.
authors.affiliation: Laboratory of Immunology, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Milner
authors.forename: Jason M
authors.initials: JM
authors.lastname: Brenchley
authors.forename: Arian
authors.initials: A
authors.lastname: Laurence
authors.forename: Alexandra F
authors.initials: AF
authors.lastname: Freeman
authors.forename: Brenna J
authors.initials: BJ
authors.lastname: Hill
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Elias
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kanno
authors.forename: Christine
authors.initials: C
authors.lastname: Spalding
authors.forename: Houda Z
authors.initials: HZ
authors.lastname: Elloumi
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Paulson
authors.forename: Joie
authors.initials: J
authors.lastname: Davis
authors.forename: Amy
authors.initials: A
authors.lastname: Hsu
authors.forename: Ava I
authors.initials: AI
authors.lastname: Asher
authors.forename: John
authors.initials: J
authors.lastname: O'Shea
authors.forename: Steven M
authors.initials: SM
authors.lastname: Holland
authors.forename: William E
authors.initials: WE
authors.lastname: Paul
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Douek
mesh_terms: D000293:Adolescent; D000328:Adult; D002176:Candida albicans / Q000276:immunology; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D004768:Enterotoxins / Q000276:immunology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis*; D007376:Interleukin-2 / Q000096:biosynthesis / Q000276:immunology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D013300:Streptokinase / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000276:immunology
chemical_list: D004768:Enterotoxins; D020381:Interleukin-17; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal; D007371:Interferon-gamma; D013300:Streptokinase