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 (T) cell differentiation and T cell metabolism. In vitro, DUSP6 CD4 T cells produced elevated IL-21. In vivo, T cells were increased in DUSP6 mice and in transgenic OTII-DUSP6 mice at steady state. After immunization, DUSP6 and OTII-DUSP6 mice generated more T 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 T cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T cell differentiation via inhibiting IL-21 production.

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