Egr2 is required for the activation of the TH17 pathogenetic program

Abstract

Abstract CD4+ TH17 lineage are a heterogenous population of CD4+ effector cells; some of which have been guardians of tissue homeostasis while others have been linked to tissue inflammation and autoimmunity. TH17 cells can alter their differentiation program ultimately giving rise to either protective non-pathogenic or pro-inflammatory pathogenic cells. Molecular switches that control the development of “pathogenic” versus “non-pathogenic” TH17 cells remain largely unknown. In this study, we identified the transcription factor Egr2 as a critical regulator of the TH17 pathogenic program. We found Egr2 was transiently expressed in the early-intermediate stage (24–48 hours) of TH17 differentiation. When ectopically expressed under TH17-polarizing conditions, Egr2 significantly enhanced the expression of TH17 signature genes in a RORγt-dependent manner. Although Egr2 was dispensable for TH17 lineage commitment, its expression was required for the generation of pathogenetic TH17 cells. Mice with T cell-specific deletion of Egr2 were less susceptible to experimental autoimmune encephalomyelitis (EAE) than WT mice. Myelin-specific Egr2-deficeint TH17 cells failed to induce a chronic inflammatory response in the CNS. Transcriptional analysis revealed that Egr2 promoted the pathogenicity of TH17 cells by regulating the expression of pathogenicity-associated genes. Interestingly, Egr2 was not required for the effector function of protective gut-resident TH17 cells in response to Citrobacter rodentium challenge. These findings indicate that Egr2 represents an attractive candidate for the therapeutic targeting of pathogenic TH17 cells while preserving tissue-protective functions of TH17 cells at barrier sites.