Division of Immunology and Allergy, Department of Paediatrics, Hospital for Sick Children and University of Toronto, Toronto, ON, Canada.
Program for Genetics & Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON, Canada.
Front Immunol. 2023 May 19;14:1183273. doi: 10.3389/fimmu.2023.1183273. eCollection 2023.
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.
We generated Stat1T385M/+ mutant mice to model the immune impacts of STAT1 DBD GOF under specific-pathogen free (SPF) conditions.
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.
Collectively, these data demonstrate that in the absence of overt infection, Stat1T385M disrupted naïve 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.
STAT1（信号转导和转录激活因子 1）是一种有效的免疫调节剂，具有功能获得性（GOF）突变的人类经常发生感染。大约三分之一的人，特别是那些具有 DNA 结合域（DBD）突变的人，如 T385M，也会发生自身免疫，有时伴随着 T-helper 1（Th1）和滤泡辅助 T（Tfh）CD4 效应 T 细胞的增加，类似于感染诱导 STAT1 信号后分化的细胞。然而，导致 STAT1 GOF 患者发生自身免疫的环境和分子机制尚不清楚。
我们构建了 Stat1T385M/+ 突变小鼠模型，在无特定病原体（SPF）条件下模拟 STAT1 DBD GOF 的免疫影响。
Stat1T385M/+ 淋巴细胞在基线时具有更多的总 Stat1，并且也具有更高量的 IFNg 诱导的 pStat1。年轻的突变体表现出 Tfh 样细胞的扩增，而老年突变体则发展为自身免疫，同时伴有 Tfh 样细胞、B 细胞激活和生发中心（GC）形成增加。突变雌性比雄性更早且更强烈地表现出这些免疫变化，确定了 Stat1T385M 诱导的免疫失调的显著性别效应。单细胞 RNA-Seq（scRNA-Seq）分析显示，Stat1T385M 在 B 和 T 细胞中激活了 GC 相关程序的转录。然而，它对 T 细胞具有最强的转录影响，促进异常 CD4 T 细胞激活，并赋予 Tfh 样和 Th1 样效应程序。
总的来说，这些数据表明，在没有明显感染的情况下，Stat1T385M 破坏了幼稚 CD4 T 细胞的稳态，并促进了异常 Tfh/Th1 样辅助和 GC 样 B 细胞的扩增和分化，最终导致性别偏倚性自身免疫，提示 STAT1 GOF 诱导的免疫失调和人类自身免疫后遗症的模型。
