title: Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells.
abstract: Hyper-IgE syndrome (HIES) is a primary immunodeficiency characterized by recurrent staphylococcal infections and atopic dermatitis associated with elevated serum IgE levels. Although defective differentiation of IL-17-producing CD4(+) T cells (Th17) partly accounts for the susceptibility to staphylococcal skin abscesses and pneumonia, the pathogenesis of atopic manifestations in HIES still remains an enigma. In this study, we examined the differentiation and function of Th1, Th2, regulatory T cells (T(reg) cells), and dendritic cells (DCs) in HIES patients carrying either STAT3 or TYK2 mutations. Although the in vitro differentiation of Th1 and Th2 cells and the number and function of T(reg) cells in the peripheral blood were normal in HIES patients with STAT3 mutations, primary and monocyte-derived DCs showed defective responses to IL-10 and thus failed to become tolerogenic. When treated with IL-10, patient DCs showed impaired up-regulation of inhibitory molecules on their surface, including PD-L1 and ILT-4, compared with control DCs. Moreover, IL-10-treated DCs from patients displayed impaired ability to induce the differentiation of naive CD4(+) T cells to FOXP3(+) induced T(reg) cells (iT(reg) cells). These results suggest that the defective generation of IL-10-induced tolerogenic DCs and iT(reg) cells may contribute to inflammatory changes in HIES.
authors.affiliation: Department of Immune Regulation, Japan Science and Technology Agency, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Saito
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nagasawa
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tsuchiya
authors.forename: Kazunaga
authors.initials: K
authors.lastname: Agematsu
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yamada
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Kawamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ariga
authors.forename: Ikuya
authors.initials: I
authors.lastname: Tsuge
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Nonoyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Karasuyama
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D015703:Antigens, CD / Q000378:metabolism; D060890:B7-H1 Antigen; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000378:metabolism* / Q000494:pharmacology; D007589:Job Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011971:Receptors, Immunologic / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D053634:TYK2 Kinase / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D016207:Cytokines; C491341:LILRB2 protein, human; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016753:Interleukin-10; D053634:TYK2 Kinase; C070139:TYK2 protein, human