CD4⁺ T helper 17 (T_H17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic T_H17 cells in the central nervous system (CNS) but not that of protective T_H17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4⁺ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the T_H17 cell transcriptional regulatory network and showed high interconnectivity with core T_H17 cell-specific transcription factors. Mechanistically, EGR2 enhanced T_H17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host’s ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic T_H17 cells in the CNS.

CD4 ⁺ T 辅助细胞 17 ( _TH 17) 细胞可保护屏障组织，但也会引发自身免疫。这些相反过程背后的机制仍不清楚。在这里，我们发现转录因子 EGR2 控制中枢神经系统 (CNS) 中致病性 T _H 17 细胞的转录程序，但不控制屏障位点的保护性 T _H 17 细胞的转录程序。来自多发性硬化症患者和患有自身免疫性神经炎症的小鼠的髓磷脂反应性 CD4 ⁺ T 细胞中的 EGR2 显着升高。 EGR2 转录程序错综复杂地编织在 T _H 17 细胞转录调控网络中，并显示出与核心 T _H 17 细胞特异性转录因子的高度互连性。从机制上讲，EGR2 通过上调发病机制相关基因和骨髓单核细胞趋化因子来增强 T _H 17 细胞分化和骨髓细胞向 CNS 的募集。 T 细胞特异性删除Egr2可减轻神经炎症，而不会损害宿主控制感染的能力。我们的研究表明，EGR2 调节中枢神经系统致病性 T _H 17 细胞的组织特异性和疾病特异性功能。