Egr2 deficiency significantly impairs the development of pathogenic TH17 cells

Abstract TH17 cells have critical functions in host defense at mucosal barriers, but they can also be the key drivers of immunopathology. Since their discovery, multiple transcription factor networks have been described that direct Th17 lineage commitment; however, molecular switches that control the development of “pathogenic” versus “non-pathogenic” TH17 cells remain largely unknown. In this study, we have identified the transcription factor Egr2 as a critical regulator of the TH17 pathogenic program. When ectopically expressed under TH17-polarizing conditions, Egr2 significantly enhanced the expression of TH17 signature genes in a RORγt-dependent manner. Although Egr2-deficient CD4+ T cells could be polarized in vitro into TH17 cells, these cells lacked the pathogenic potential in a TH17-dependent disease model, experimental autoimmune encephalomyelitis (EAE). In both active EAE and passive EAE, Egr2-deficeint TH17 cells failed to induce neuroinflammatory response in the CNS. Analysis of CNS infiltrates revealed reduced accumulation of IL-17A-producing CD4+ T cells and impaired recruitment of monocytes and myeloid dendritic cells in mice with T cell-specific loss of Egr2. Most importantly, transcriptional analysis of ex vivo isolated Egr2-deficient CD4+ T cells revealed that Egr2 controlled the expression of pathogenicity-associated genes in TH17 cells in the CNS. We further show that Egr2 deficiency did not affect the effector function of protective TH17 cells at mucosal barriers in Citrobacter rodentium and Candida albicans infections, suggesting that Egr2 is an attractive candidate for the therapeutic targeting of pathogenic TH17 cells while preserving tissue-protective functions of TH17 cells at barrier sites.