title: Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations.
abstract: BACKGROUND
  Gain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of signal transducer and activator of transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease. This condition is characterized by fungal and bacterial infections caused by impaired generation of TH17 cells; meanwhile, some patients with chronic mucocutaneous candidiasis disease might also have viral or intracellular pathogen infections.
  
  
  OBJECTIVE
  We sought to investigate the effect of STAT1 GOF mutations on the functioning of natural killer (NK) cells.
  
  
  METHODS
  Because STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in 8 patients with STAT1 GOF mutations.
  
  
  RESULTS
  Functional analysis of NK cells shows a significant impairment of cytolytic and degranulation activities in patients with STAT1 GOF mutations. Moreover, NK cells from these patients display lower production of IFN-γ in response to IL-15 and reduced proliferation after stimulation with IL-2 or IL-15, suggesting that STAT5 signaling is affected. In addition, signaling studies demonstrate that the increased phosphorylation of STAT1 in response to IFN-α is associated with detectable activation of STAT1 and increased STAT1 binding to the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) promoter in response to IL-15, whereas STAT5 phosphorylation and DNA binding to IL-2 receptor α (IL2RA) are reduced or not affected in response to the same cytokine.
  
  
  CONCLUSIONS
  These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Tabellini
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Vairo
authors.affiliation: Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy.
authors.forename: Omar
authors.initials: O
authors.lastname: Scomodon
authors.affiliation: Department of Medicine, Section of General Pathology, School of Medicine, University of Verona, Verona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tamassia
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy.
authors.forename: Rosalba Monica
authors.initials: RM
authors.lastname: Ferraro
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Ornella
authors.initials: O
authors.lastname: Patrizi
authors.affiliation: Department of Medicine, Section of General Pathology, School of Medicine, University of Verona, Verona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Gasperini
authors.affiliation: Unit of Paediatrics, Spedali Civili of Brescia, Brescia, Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Soresina
authors.affiliation: Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.
authors.forename: Giuliana
authors.initials: G
authors.lastname: Giardino
authors.affiliation: Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pignata
authors.affiliation: Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Lougaris
authors.affiliation: Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.affiliation: Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Dotta
authors.affiliation: Department of Medicine, Section of General Pathology, School of Medicine, University of Verona, Verona, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cassatella
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parolini
authors.affiliation: Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy. Electronic address: raffaele.badolato@unibs.it.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Badolato
mesh_terms: D000293:Adolescent; D000328:Adult; D002178:Candidiasis, Chronic Mucocutaneous / Q000235:genetics* / Q000276:immunology; D002648:Child; D016207:Cytokines / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006801:Humans; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism
chemical_list: D016207:Cytokines; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050799:STAT5 Transcription Factor
keywords: IL-15; Natural killer cells; candidiasis; cytotoxic activity; signal transducer and activator of transcription 1; signal transducer and activator of transcription 5