Early Growth Response Gene-2 Controls Inflammatory Responses of CD4+ T Cells by Negatively Regulating Th17 Differentiation.

Abstract

CD4+ T cells play a central role in controlling the adaptive immune response by secreting cytokines to control the responses of different lymphocytes. Naïve CD4+ T cells differentiate into at least four subsets, Th1, Th2, Th17, and inducible regulatory T cells under antigen and corresponding cytokine microenvironment during an immune response. Therefore, each subset has unique functions for pathogen elimination. The differentiation of these subsets is induced in response to conditioned cytokine stimulation, which induces specific master regulator transcription factors. Multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. Previously, our group has discovered that early growth response gene-2 (Egr-2) is important for the maintenance of T cell homeostasis and controls the development of autoimmune disease. However, the underlying mechanisms are unknown. In this study, using Egr-2 conditional knockout mice, a novel mechanism of Egr-2 in the control of Th17 differentiation has been discovered. Egr-2 is induced by TGFβ and IL-6 in naïve CD4+ T cells. The induced Egr-2 negatively regulates the expression of IL-17, the signature cytokine for Th17. In contrast, Egr-2 has less effect on the expression of IL-2 or IFN-γ in effector T cells. In the absence of Egr-2, CD4+ T cells produce high levels of Th17 cytokines. Deletion of Egr-2 in T cells renders mice susceptible to EAE induction; a model for Th17 mediated autoimmune diseases. T cells lacking Egr-2 show increased propensity for Th17, but not Th1 or Th2, differentiation in vitro. The key mechanism of Egr-2 in regulation of Th17 differentiation is to inhibit the function of Batf for transactivation of IL-17 expression and promotion of Th17 differentiation. Egr-2 interacts with Batf in CD4+ T cells and suppresses its interaction with DNA sequences derived from the IL-17 promoter, while the activation of STAT3 and expression of RORγt is unchanged in Th17 cells in the absence of Egr-2. Thus, Egr- 14 2 plays an important role to intrinsically control Th17 differentiation. We also found that CD4+ T cells from multiple sclerosis (MS) patients have reduced expression of Egr-2 and increased expression of IL-17 following stimulation with anti-CD3 in vitro. Collectively, our results demonstrate that Egr-2 is an intrinsic regulator that controls Th17 differentiation by inhibiting Batf activation which may be important for the control of inflammatory autoimmune diseases.