Center for Fundamental Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA.
JCI Insight. 2022 Jun 22;7(12):e148222. doi: 10.1172/jci.insight.148222.
The transcription factor STAT1 plays a critical role in modulating the differentiation of CD4+ T cells producing IL-17 and GM-CSF, which promote the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). The protective role of STAT1 in MS and EAE has been largely attributed to its ability to limit pathogenic Th cells and promote Tregs. Using mice with selective deletion of STAT1 in T cells (STAT1CD4-Cre), we identified a potentially novel mechanism by which STAT1 regulates neuroinflammation independently of Foxp3+ Tregs. STAT1-deficient effector T cells became the target of NK cell-mediated killing, limiting their capacity to induce EAE. STAT1-deficient T cells promoted their own killing by producing more IL-2 that, in return, activated NK cells. Elimination of NK cells restored EAE susceptibility in STAT1CD4-Cre mice. Therefore, our study suggests that the STAT1 pathway can be manipulated to limit autoreactive T cells during autoimmunity directed against the CNS.
转录因子 STAT1 在调节产生 IL-17 和 GM-CSF 的 CD4+T 细胞的分化中发挥关键作用，这些细胞促进实验性自身免疫性脑脊髓炎（EAE）的发展，EAE 是多发性硬化症（MS）的动物模型。STAT1 在 MS 和 EAE 中的保护作用主要归因于其限制致病性 Th 细胞和促进 Tregs 的能力。我们使用 T 细胞中选择性缺失 STAT1 的小鼠（STAT1CD4-Cre），发现了一种 STAT1 调节神经炎症的潜在新机制，该机制独立于 Foxp3+Tregs。STAT1 缺陷效应 T 细胞成为 NK 细胞介导杀伤的靶标，限制了它们诱导 EAE 的能力。STAT1 缺陷 T 细胞通过产生更多的 IL-2 来促进自身杀伤，而 IL-2 反过来又激活了 NK 细胞。消除 NK 细胞恢复了 STAT1CD4-Cre 小鼠对 EAE 的易感性。因此，我们的研究表明，STAT1 途径可以在针对中枢神经系统的自身免疫中被操纵以限制自身反应性 T 细胞。
