| First Author | Largent AD | Year | 2023 |
| Journal | Sci Transl Med | Volume | 15 |
| Issue | 703 | Pages | eade7028 |
| PubMed ID | 37406138 | Mgi Jnum | J:338134 |
| Mgi Id | MGI:7509669 | Doi | 10.1126/scitranslmed.ade7028 |
| Citation | Largent AD, et al. (2023) Dysregulated IFN-gamma signals promote autoimmunity in STAT1 gain-of-function syndrome. Sci Transl Med 15(703):eade7028 |
| abstractText | Heterozygous signal transducer and activator of transcription 1 (STAT1) 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(H)1-skewed CXCR3(+) populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1(GOF) 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, Stat1(GOF) 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, Stat1(GOF) mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-gamma) signals abrogated autoimmunity. Last, germline STAT1 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-gamma receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-gamma as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome. |
