AMP kinase promotes Bcl6 expression in both mouse and human T cells

Abstract

The transcription factor Bcl6 is a master regulator of follicular helper T (TFH) cells, and understanding the signaling pathway that induces Bcl6 and TFH cell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how TFH 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 TFH–dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in TFH cells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of TFH cell marker expression by human CD4 T cells. Our data reveal a major new pathway for TFH cell differentiation, conserved by both mouse and human T cells. Mature TFH cells are reported to have a lower metabolic state compared to TH1 cells. Our data indicates that decreased metabolism may be deterministic for TFH cell differentiation, and not simply a result of TFH cell differentiation.

Inhibition of stearoyl‐CoA desaturases suppresses follicular help T‐ and germinal center B‐ cell responses

“…Interestingly, recent evidence suggests that cell metabolic processes may play important roles in modulating T FH development in vivo. BCL6 was shown to repress glycolysis in activated CD4 + T cells [5, 6]. Consistently, it has been demonstrated that T FH cells exhibit diminished glycolysis and mitochondrial respiration compared to T H1 cells [7].…”

Follicular regulatory T cells inhibit the development of granzyme B–expressing follicular helper T cells

“…Total RNA was collected from freshly sorted cells using the RNeasy Plus Micro kit (QIAGEN). qPCR reactions were performed as previously reported (32).…”

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

“…However, it has also been shown that expression of Bcl6 represses the glycolytic gene program (38). Consistent with this, inhibition of glycolysis pathway or glucose deprivation does not block Bcl6expressing T FH cell differentiation (39). The findings reveal a controversial role of glycolysis during T FH differentiation and suggest that glycolysis might be required for early T cell activation, but optional for differentiated mature T FH cells.…”