The lack of either IRF9, or STAT2, has surprisingly little effect on human natural killer cell development and function

Abstract

Analysis of genetically defined immunodeficient patients allows study of the effect of the absence of specific proteins on human immune function in real-world conditions. Here we have addressed the importance of type I interferon signalling for human NK cell development by studying the phenotype and function of circulating NK cells isolated from patients suffering primary immunodeficiency disease due to mutation of either the human interferon regulatory factor 9 (IRF9) or the signal transducer and activator of transcription 2 (STAT2) genes. IRF9, together with phosphorylated STAT1 and STAT2, form a heterotrimer called interferon stimulated gene factor 3 (ISGF3) which promotes the expression of hundreds of IFN-stimulated genes that mediate antiviral function triggered by exposure to type I interferons. IRF9- and STAT2-deficient patients are unable to respond efficiently to stimulation by type I interferons and so our experiments provide insights into the importance of type I interferon signalling and the consequences of its impairment on human NK cell biology. Surprisingly, the NK cells of these patients display essentially normal phenotype and function.This original article investigates the role of type I interferon signaling in human natural killer cell development and function using samples from patients with genetically defined IRF9 or STAT2 deficiency. Because IRF9 and STAT2 are key components of the ISGF3 complex required for type I interferon–induced antiviral gene expression, these patients provide a human model to assess the consequences of impaired IFN-I signaling on NK-cell biology. The study shows that circulating NK cells from IRF9- and STAT2-deficient patients display broadly normal phenotype, receptor expression, HLA class I expression, granzyme B/perforin content, degranulation and IFN-γ production. These findings suggest that, unexpectedly, direct type I interferon signaling through IRF9 or STAT2 has limited impact on human NK-cell development and baseline function.