Department of Rheumatology and Immunology, Drum Tower Clinical Medical College of Nanjing Medical University, Nanjing, China.
Department of Rheumatology and Immunology, Fujian Provincial Hospital, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
Front Immunol. 2021 Jul 29;12:675542. doi: 10.3389/fimmu.2021.675542. eCollection 2021.
Autoreactive T cells play a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). TGF-β type I receptor (TGFβRI) is pivotal in determining T cell activation. Here, we showed that TGFβRI expression in naïve CD4 T cells was decreased in SLE patients, especially in those with high disease activity. Moreover, IL-6 was found to downregulate TGFβRI expression through JAK/STAT3 pathway in SLE patients. , the JAK inhibitor tofacitinib inhibited SLE T cell activating by upregulating TGFβRI expression in a dose-dependent manner. In MRL/lpr mice, tofacitinib treatment ameliorated the clinical indicators and lupus nephritis, as evidenced by reduced plasma anti-dsDNA antibody levels, decreased proteinuria, and lower renal histopathological score. Consistently, tofacitinib enhanced TGFβRI expression and inhibited T cell activation . TGFβRI inhibitor SB431542 reversed the effects of tofacitinib on T cell activation. Thus, our results have indicated that tofacitinib can suppress T cell activation by upregulating TGFβRI expression, which provides a possible molecular mechanism underlying clinical efficacy of tofacitinib in treating SLE patients.
自身反应性 T 细胞在系统性红斑狼疮 (SLE) 的发病机制中起着至关重要的作用。TGF-β 型 I 受体 (TGFβRI) 在决定 T 细胞激活中起着关键作用。在这里，我们表明，SLE 患者幼稚 CD4 T 细胞中的 TGFβRI 表达降低，尤其是在疾病活动度高的患者中。此外，研究发现 IL-6 通过 JAK/STAT3 通路下调 SLE 患者中 TGFβRI 的表达。JAK 抑制剂托法替尼通过上调 TGFβRI 表达以剂量依赖性方式抑制 SLE T 细胞激活。在 MRL/lpr 小鼠中，托法替尼治疗改善了临床指标和狼疮肾炎，表现为血浆抗 dsDNA 抗体水平降低、蛋白尿减少和肾脏组织病理学评分降低。一致地，托法替尼增强了 TGFβRI 的表达并抑制了 T 细胞的激活。TGFβRI 抑制剂 SB431542 逆转了托法替尼对 T 细胞激活的影响。因此，我们的结果表明，托法替尼可以通过上调 TGFβRI 表达来抑制 T 细胞激活，这为托法替尼治疗 SLE 患者的临床疗效提供了可能的分子机制。
