期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2018
卷号：115
期号：34
页码：E8027-E8036
DOI：10.1073/pnas.1800076115
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 inhibiting IL-21 production.
关键词：DUSP6 ; follicular helper T cells ; IL-21 ; glycolysis ; T cell metabolism
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