The transcription factor Bcl6 is a master regulator of follicular helper T (T_FH) cells, and understanding the signaling pathway that induces Bcl6 and T_FH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how T_FH cells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong T_FH–dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in T_FH cells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of T_FH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for T_FH cell differentiation, conserved by both mouse and human T cells. Mature T_FH cells are reported to have a lower metabolic state compared to T_H1 cells. Our data indicates that decreased metabolism may be deterministic for T_FH cell differentiation, and not simply a result of T_FH cell differentiation.