Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome

Abstract

Heterozygous signal transducer and activator of transcription 1 (<i>STAT1</i>) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4⁺ T cell and B cell activation, including expansion of T_H1-skewed CXCR3⁺ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated <i>Stat1</i> GOF transgenic mice (<i>Stat1^GOF</i> mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (T_reg) deficiency, <i>Stat1^GOF</i> mice and humans with STAT1 GOF syndrome exhibited normal T_reg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, <i>Stat1^GOF</i> mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline <i>STAT1</i> GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome.