干扰素颠覆AHR-JUN轴以促进狼中的CXCL13+T细胞
Calvin Law1,2,3,4,5, Vanessa Sue Wacleche6, Ye Cao6
1Department of Biochemistry and Molecular Genetics, The Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Nature
|July 10, 2024
概括
系统性红斑狼 (SLE) 涉及异常的T细胞相互作用. 研究人员发现,基碳水化合物受体 (AHR) 调节T细胞表型,影响疾病途径并提供新的治疗点.
科学领域:
- 免疫学
- 自身免疫性疾病
- 分子生物学
背景情况:
- 系统性红斑狼 (SLE) 的特征是异常的T细胞与B细胞相互作用.
- 产生CXCL13的T毛囊辅助细胞 (TFH) 和外围T辅助细胞 (TPH) 的扩张是SLE的标志.
- 目前尚不完全了解T细胞CXCL13生成的调节及其与SLE中其他T细胞状态的关系.
研究的目的:
- 在SLE患者中研究CD4+T细胞表型的失衡.
- 确定T细胞中CXCL13产生的关键调节剂.
- 阐明SLE中控制T细胞两极化的分子机制.
主要方法:
- 通过CRISPR选来识别CXCL13生产的调节者.
- 转录组,表观遗传和功能测试.
- 在SLE患者中分析CD4+T细胞群 (PD-1+/ ICOS+,CD96hi IL-22+).
主要成果:
- 在SLE患者中观察到PD-1+/ ICOS+ CXCL13+ T细胞的扩张和CD96hi IL-22+ T细胞的减少.
- 亚利碳水化合物受体 (AHR) 被确定为CD4+ T细胞CXCL13生成的负调节剂.
- AHR与JUN协调,抑制TPH/TFH分化并促进IL-22+T细胞的分化,而I型干扰素则反对这种作用.
结论:
- 在预防CXCL13+ TPH/ TFH细胞的分化和促进IL-22+ T细胞方面,AHR和JUN具有关键作用.
- 一类干扰素对抗AHR和JUN,驱动CXCL13的产生.
- 这些发现为SLE中不同的T细胞状态 (CXCL13+ TPH/ TFH与T辅助22细胞) 建立了调控轴.
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