DUSP6 has been demonstrated to restrict T helper 1 (T H 1) cell differentiation through regulation of ERK1/2-phosphorylation. Here we reported novel roles of DUSP6 in the regulation of follicular helper T (T FH ) cell differentiation and T cell metabolism utilizing DUSP6 knockout (KO) mice. Under T FH cell-differentiation condition, DUSP6-deficient CD4 + T cells produced increased amounts of IL-21, the determinant cytokine directing T FH cell generation. The population of T FH cells increased in the steady state in KO mice, which were associated with an increase of germinal center (GC) B cells. Remarkably, DUSP6-deficient T cells showed a stronger T cell receptor (TCR)-mediated JNK- and p38-phosphorylation. Meanwhile, TCR-in-duced ERK-phosphorylation was marginally affected. Treatment wit DUSP6 inhibitor in Jurkat T cells led to increases of TCR-mediated JNK-and p38-phosphorylation, suggesting that DUSP6 preferentially targeted JNK and p38 in T cells. The increased production of IL-21 in DUSP6-deficient T cells was significantly abolished with the supplement of JNK inhibitor or p38 inhibitor. Unexpectedly, DUSP6-deficient T cells exhibited an impaired glycolysis in the steady state and upon TCR-stimulation. The impaired glycolysis in DUSP6-deficient T cells was not caused by the stronger TCR-mediated JNK- or p38-activation, but due to an impaired activity of phosphofructokinase (PFK), which catalyzes the rate limiting step in the glycolysis pathway. Different than WT T cells, DUSP6-deficient T cells showed a stronger energy fueldependence on glutamine and/or fatty acid. Our data suggest that DUSP6 plays essential roles in effector T cell differentiation and T cell metabolism in various aspects. First, DUSP6 suppresses TCR-mediated JNK- and p38-activation that restrains T FH cell differentiation in the steady state. Secondly, DUSP6 is positively required for the maximal induction of TCR-mediated PFK activation and glycolysis. Thirdly, TCR-induced glycolysis is dispensable for T FH cell differentiation, as long as the alternative energy source such as glutamine or fatty acid is available.
