72 : EGR2 is critical for peripheral Naïve T cell differentiation and the T-cell mediated response to influenza

Abstract

EGR1 and EGR2 are closely related members of an early growth response family of transcription factors, with EGR1 generally considered to be a positive regulator and EGR2 a negative regulator of T cell activation, promoting T cell anergy while decreasing autoimmunity. Here, we have studied the roles of these factors during influenza infection and unexpectedly found that EGR2, but not EGR1, is required for peripheral naive T cell differentiation and T cell-mediated immune responses. Deletion of either the Egr1 or Egr2 gene delayed TCR-induced proliferation of peripheral naive CD4+ and CD8+ T cells, with Egr2 -deficient T cells having lower proliferation and cytokine expression than Egr1 -deficient T cells, with lower IFN- γ , IL-4, IL-9, and IL-17A expression under Th1, Th2, Th9, and Th17 conditions, respectively. Moreover, Egr2 was necessary for T cellmediated immune responses to influenza infection, with delayed virus clearance, greater weight loss, and more severe pathologic changes in Egr2 conditional KO (CKO) mice than in WT or Egr1 KO mice. The Egr2 CKO mice also had defective CD4+ T cell immune responses, with dysregulated cytokine expression and augmented infiltration of antigen-specific CD8+ T cells that had a memory precursor phenotype and decreased cytolytic activity. Collectively, these results unexpectedly reveal that EGR2 is an essential transcriptional regulator for the differentiation of naive T cells and a critical positive regulator of the normal T cell-mediated immune response to influenza infection.