Transcription factor EGR2 controls homing and pathogenicity of T H 17 cells in the central nervous system.

CD4 + T helper 17 (T H 17) 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 H 17 cells in the central nervous system (CNS) but not that of protective T H 17 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 H 17 cell transcriptional regulatory network and showed high interconnectivity with core T H 17 cell-specific transcription factors. Mechanistically, EGR2 enhanced T H 17 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 H 17 cells in the CNS.