DUSP6 mediates T cell receptor-engaged glycolysis and restrains TFH cell differentiation

Wei Chan Hsu, Ming Yu Chen, Shu Ching Hsu, Li Rung Huang, Cheng Yuan Kao, Wen Hui Cheng, Chien Hsiung Pan, Ming Sian Wu, Guann Yi Yu, Ming Shiu Hung, Chuen Miin Leu, Tse Hua Tan, Yu Wen Su*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Activated T cells undergo metabolic reprogramming and effector-cell differentiation but the factors involved are unclear. Utilizing mice lacking DUSP6 (DUSP6/), we show 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. 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. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains TFH cell differentiation via inhibitin IL-21 Production.

Original languageEnglish
Pages (from-to)E8027-E8036
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number34
DOIs
StatePublished - 21 Aug 2018

Keywords

  • DUSP6
  • Follicular helper T cells
  • Glycolysis
  • IL-21
  • T cell metabolism

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