| First Author | Scott O | Year | 2023 |
| Journal | Front Immunol | Volume | 14 |
| Pages | 1183273 | PubMed ID | 37275873 |
| Mgi Jnum | J:346984 | Mgi Id | MGI:7488933 |
| Doi | 10.3389/fimmu.2023.1183273 | Citation | Scott O, et al. (2023) The human Stat1 gain-of-function T385M mutation causes expansion of activated T-follicular helper/T-helper 1-like CD4 T cells and sex-biased autoimmunity in specific pathogen-free mice. Front Immunol 14:1183273 |
| abstractText | INTRODUCTION: Humans with gain-of-function (GOF) mutations in STAT1 (Signal Transducer and Activator of Transcription 1), a potent immune regulator, experience frequent infections. About one-third, especially those with DNA-binding domain (DBD) mutations such as T385M, also develop autoimmunity, sometimes accompanied by increases in T-helper 1 (Th1) and T-follicular helper (Tfh) CD4 effector T cells, resembling those that differentiate following infection-induced STAT1 signaling. However, environmental and molecular mechanisms contributing to autoimmunity in STAT1 GOF patients are not defined. METHODS: We generated Stat1T385M/+ mutant mice to model the immune impacts of STAT1 DBD GOF under specific-pathogen free (SPF) conditions. RESULTS: Stat1T385M/+ lymphocytes had more total Stat1 at baseline and also higher amounts of IFNg-induced pStat1. Young mutants exhibited expansion of Tfh-like cells, while older mutants developed autoimmunity accompanied by increased Tfh-like cells, B cell activation and germinal center (GC) formation. Mutant females exhibited these immune changes sooner and more robustly than males, identifying significant sex effects of Stat1T385M-induced immune dysregulation. Single cell RNA-Seq (scRNA-Seq) analysis revealed that Stat1T385M activated transcription of GC-associated programs in both B and T cells. However, it had the strongest transcriptional impact on T cells, promoting aberrant CD4 T cell activation and imparting both Tfh-like and Th1-like effector programs. DISCUSSION: Collectively, these data demonstrate that in the absence of overt infection, Stat1T385M disrupted naive CD4 T cell homeostasis and promoted expansion and differentiation of abnormal Tfh/Th1-like helper and GC-like B cells, eventually leading to sex-biased autoimmunity, suggesting a model for STAT1 GOF-induced immune dysregulation and autoimmune sequelae in humans. |
