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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 H 1 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., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Recent evidence has identified the role of granzyme B- and perforin-expressing CD4(+) T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4(+) T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4(+) T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4(+) T cells and was required for the cytolytic function of the in vitro- and in vivo-generated CD4(+) T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed.