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

作者：Andrea D. Largent, Katharina Lambert, Kristy Chiang, Natali Shumlak, Denny Liggitt, Mohammed Oukka, Troy R. Torgerson, Jane H. Buckner, Eric J. Allenspach, David J. Rawlings, Shaun W. Jackson · 发表于：Science Translational Medicine · 年份：2023 · DOI：10.1126/scitranslmed.ade7028 · 被引用次数：33 · 研究领域：Immunodeficiency and Autoimmune Disorders、Immune Cell Function and Interaction、T-cell and B-cell Immunology

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-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are tho...