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 (T(FH)) cell differentiation and T cell metabolism. In vitro, DUSP6(-/-) CD4(+) T(FH) cells produced elevated IL-21. In vivo, T(FH) 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(FH) 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(FH) cells. Our findings suggest that DUSP6 connects TCR signaling to activation-induced metabolic commitment toward glycolysis and restrains T(FH) cell differentiation via inhibiting IL-21 production.