Impaired NK cell functions in patients with STAT1 gain-of-function mutations

Publication date: Available online 6 January 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Giovanna Tabellini, Donatella Vairo, Omar Scomodon, Nicola Tamassia, Rosalba Monica Ferraro, Ornella Patrizi, Sara Gasperini, Annarosa Soresina, Giuliana Giardino, Claudio Pignata, Vassilios Lougaris, Alessandro Plebani, Laura Dotta, Marco A. Cassatella, Silvia Parolini, Raffaele Badolato
BackgroundGain-of-function (GOF) mutations affecting the coiled-coil domain or the DNA-binding domain of the Signal Transducer and Activator of Transcription 1 (STAT1) cause chronic mucocutaneous candidiasis disease (CMCD). This condition is characterized by fungal and bacterial infections due to impaired generation of Th17 cells; meanwhile some CMCD patients may also develop viral or intracellular pathogens infections.ObjectiveTo Investigate the effect of GOF-STAT1 mutations on functioning of Natural Killer (NK) cells.MethodsSince STAT1 is involved in the signaling response to several cytokines, we studied NK cell functional activities and STAT1 signaling in eight patients with STAT1-GOF mutations.ResultsFunctional 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 IFIT1 promoter in response to IL-15, while STAT5 phosphorylation and DNA binding to IL2RA are reduced or not affected in response to the same cytokine.ConclusionThese observations suggest that persistent activation of STAT1 might affect NK cell proliferation and functional activities.

Teaser

Gain-of-function (GOF) mutations of the Signal Transducer and Activator of Transcription 1 (STAT1) resulting in increased phosphorylation of the protein lead to chronic mucocutaneous candidiasis disease (CMCD). Abnormal signaling of STAT1 results in impaired response of NK cells to IL-15, leading to defects of proliferation, IFN-γ production and cytolytic activity that may contribute to the increased susceptibility of patients with STAT1-GOF mutations to viruses and intracellular pathogens.


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