DUSP6, a MAPK phosphatase has been shown to regulate MAPK activities, including those of ERK, JNK, and p38. Dr. Yu-Wen Su and her team from the Immunology Research center utilized mice lacking DUSP6 (DUSP6−/−) and demonstrated that this phosphatase regulates T cell receptor (TCR) signaling to influence follicular helper T (TFH) cell differentiation and T cell metabolism. In vitro, DUSP6−/− CD4+ TFH cells produced elevated IL-21. In vivo, TFH cells were increased in DUSP6−/− mice and in transgenic OTII-DUSP6−/− mice at steady state. After immunization, DUSP6−/− and OTII-DUSP6−/− mice generated more TFH cells and produced more antigen-specific IgG2 than controls. Activated DUSP6−/− T cells showed enhanced JNK and p38 phosphorylation but impaired glycolysis. JNK or p38 inhibitors significantly reduced IL-21 production but did not restore glycolysis. In addition, TCR-stimulated DUSP6−/− T cells could not induce phosphofructokinase activity and relied on glucose-independent fueling of mitochondrial respiration. Upon CD28 costimulation, activated DUSP6−/− T cells did not undergo the metabolic commitment to glycolysis pathway to maintain viability. Unexpectedly, inhibition of fatty acid oxidation drastically lowered IL-21 production in DUSP6−/− TFH cells.
Dr. Su’s team demonstrated a role for DUSP6 in the glycolysis commitment during T cell activation. DUSP6 deficiency prompts activated T cells to rely on glucose-independent fuels. The team also showed that DUSP6 fine-tunes TCR-MAPK signaling, which determines follicular helper T (TFH) effector-cell differentiation regardless of a glycolytic defect. These findings imply that glycolysis is required for survival of activated T cells but optional for IL-21 production in TFH cell differentiation.
Citation: Hsu, WC;Chen, MY;Hsu, SC;Huang, LR;Kao, CY;Cheng, WH;Pan, CH;Wu, MS;Yu, GY;Hung, MS;Leu, CM;Tan, TH;Su, YW. DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation. Proceedings of the National Academy of Sciences of the United States of America. 2018 Aug 21;115(34):E8027-E8036.