title: Dedicator of cytokinesis 8 regulates signal transducer and activator of transcription 3 activation and promotes TH17 cell differentiation.
abstract: The autosomal recessive hyper-IgE syndrome (HIES) caused by dedicator of cytokinesis 8 (DOCK8) deficiency shares clinical features with autosomal dominant HIES because of signal transducer and activator of transcription 3 (STAT3) mutations, including recurrent infections and mucocutaneous candidiasis, which are suggestive of TH17 cell dysfunction. The mechanisms underlying this phenotypic overlap are unclear.
  
  
  
  We sought to elucidate common mechanisms operating in the different forms of HIES.
  
  
  
  We analyzed the differentiation of CD4+THcell subsets in control and DOCK8-deficient subjects. We also examined the role of DOCK8 in regulating STAT3 activation in T cells. THcell differentiation was analyzed by ELISA, flow cytometry, and real-time PCR measurements of cytokines and THcell transcription factors. The interaction of DOCK8 and STAT3 signaling pathways was examined by using flow cytometry, immunofluorescence, coimmunoprecipitation, and gene expression analysis.
  
  
  
  There was a profound block in the differentiation of DOCK8-deficient naive CD4+T cells into TH17 cells. A missense mutation that disrupts DOCK8 guanine nucleotide exchange factor (GEF) activity while sparing protein expression also impaired TH17 cell differentiation. DOCK8 constitutively associated with STAT3 independent of GEF activity, whereas it regulated STAT3 phosphorylation in a GEF activity-dependent manner. DOCK8 also promoted STAT3 translocation to the nucleus and induction of STAT3-dependent gene expression.
  
  
  
  DOCK8 interacts with STAT3 and regulates its activation and the outcome of STAT3-dependent TH17 differentiation. These findings might explain the phenotypic overlap between DOCK8 deficiency and autosomal dominant HIES.
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
authors.forename: Sevgi
authors.initials: S
authors.lastname: Keles
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Louis Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.affiliation: Program in Molecular and Cellular Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Venkataraman
authors.initials: V
authors.lastname: Kabaleeswaran
authors.affiliation: Division of Pediatric Immunology and Allergy, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey.
authors.forename: Ismail
authors.initials: I
authors.lastname: Reisli
authors.affiliation: Division of Pediatric Immunology, Behcet Uz State Hospital, Izmir, Turkey.
authors.forename: Ferah
authors.initials: F
authors.lastname: Genel
authors.affiliation: Division of Pediatric Immunology, Behcet Uz State Hospital, Izmir, Turkey.
authors.forename: Nesrin
authors.initials: N
authors.lastname: Gulez
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait.
authors.forename: Waleed
authors.initials: W
authors.lastname: Al-Herz
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Ramesh
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez-Atayde
authors.affiliation: Division of Pediatric Immunology, Ege University, Izmir, Turkey.
authors.forename: Neslihan E
authors.initials: NE
authors.lastname: Karaca
authors.affiliation: Division of Pediatric Immunology, Ege University, Izmir, Turkey.
authors.forename: Necil
authors.initials: N
authors.lastname: Kutukculer
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass; Program in Molecular and Cellular Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
authors.forename: Raif S
authors.initials: RS
authors.lastname: Geha
authors.affiliation: Division of Immunology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Mass. Electronic address: talal.chatila@childrens.harvard.edu.
authors.forename: Talal A
authors.initials: TA
authors.lastname: Chatila
mesh_terms: D001323:Autoantibodies / Q000276:immunology; D002454:Cell Differentiation; D002648:Child; D002675:Child, Preschool; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007223:Infant; D019169:Jurkat Cells; D008297:Male; D009154:Mutation; D010766:Phosphorylation; D021381:Protein Transport; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D001323:Autoantibodies; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: Cell division cycle 42; T(H)17; dedicator of cytokinesis 8; guanine nucleotide exchange factor; hyper-IgE syndrome; mucocutaneous candidiasis; signal transducer and activator of transcription 3; suppressor of cytokine signaling 3