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

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 inhibitin IL-21 Production.