Giovanna Tabellini1, Donatella Vairo2, Omar Scomodon3, Nicola Tamassia4, Rosalba Monica Ferraro2, Ornella Patrizi1, Sara Gasperini4, Annarosa Soresina5, Giuliana Giardino6, Claudio Pignata6, Vassilios Lougaris3, Alessandro Plebani3, Laura Dotta3, Marco A Cassatella4, Silvia Parolini1, Raffaele Badolato7. 1. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. 2. Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy. 3. Institute of Molecular Medicine "Angelo Nocivelli," University of Brescia, Brescia, Italy; Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy. 4. Department of Medicine, Section of General Pathology, School of Medicine, University of Verona, Verona, Italy. 5. Unit of Paediatrics, Spedali Civili of Brescia, Brescia, Italy. 6. Department of Translational Medical Sciences, Federico II University of Naples, Naples, Italy. 7. 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.
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. CONCLUSION: These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.
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. CONCLUSION: These observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.
Keywords:
IL-15; Natural killer cells; candidiasis; cytotoxic activity; signal transducer and activator of transcription 1; signal transducer and activator of transcription 5
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