MicroRNA-21 Regulates Metabolic Adaptation of Pathogenic T_H17 cells and Controls Autoimmune Inflammation

Abstract

T_H17 cells exhibit great heterogeneity and variable functional states in vivo. However, the precise molecular mechanism for this heterogeneity is poorly understood. Here we demonstrate that homeostatic and pathogenic T_H17 cells in vivo show discrete chromatin states at conserved regulatory region of T_H17 cell-related transcription factors, metabolic regulators and microRNAs. We find the regulatory region of miR-21 shows great more chromatin accessibility in CNS infiltrating pathogenic T_H17 cells compared to ileum homeostatic T_H17 cells. We further demonstrate that homeostatic and pathogenic T_H17 cells have distinct metabolic states, and miR-21 is essential for the highly glycolytic state of pathogenic T_H17 cells. MiR-21-deficient T_H17 cells show less glycolytic activity and express less pathogenic T_H17 cell signature genes. These findings suggest that miR-21 is a critical regulator for the metabolic adaptation of pathogenic T_H17 cells under autoimmune inflammation.