Bcl-6 directly represses the gene program of the glycolysis pathway

Abstract

Despite our increasing knowledge of the molecular events that induce the glycolysis pathway in effector T cells, very little is known about the transcriptional mechanisms that dampen the glycolysis program in quiescent cell populations such as memory T cells. Here, we show that the transcription factor Bcl-6 directly repressed genes involved in the glycolysis pathway, including Slc2a1, Slc2a3, Pkm2 and Hk2, in TH1 cells exposed to low amounts of interleukin 2 (IL-2). Thus, Bcl-6 plays an opposing role to the IL-2-sensitive glycolytic transcriptional program that c-Myc and HIF-1α promote in effector T cells. Additionally, the Th1-lineage-specifying factor T-bet functionally antagonized the Bcl-6-dependent repression of genes in the glycolysis pathway, implicating the molecular balance between these two factors in metabolic gene program regulation.

Immunometabolism: Cellular Metabolism Turns Immune Regulator

“…The data also suggest that mTORC1 has an important role for cytokineinduced glycolysis in NK cells (22). A number of transcription factors are involved in glycolytic reprogramming of T cells including both hypoxia-inducible factor 1␣ (HIF1␣) and c-Myc (9,25,26). In B cells, c-Myc but not HIF1␣ is important for the glycolytic response (21).…”

Harnessing the plasticity of CD4+ T cells to treat immune-mediated disease

“…HIF1α has a particularly important role in T H 17 cell polarization, for which, in addition to promoting glycolysis, it directly induces the expression of RORγt and supports its function 102,104 . The transcriptional activity of HIF1α is also opposed by the transcriptional repressor BCL-6 (B cell lymphoma 6), which competes for binding to many of the same genes, preventing the induction of glycolytic genes that may be detrimental to the T FH cell programme 105 .…”

T cell metabolism drives immunity

“…Signaling through mTORC1 versus mTORC2 also selectively differentiates CD4 T cells into the Th1 and Th2 lineages, respectively (Lee et al, 2010;Delgoffe et al, 2011), although activation of mTORC1 and its component Raptor is still required for T cell exit from quiescence to begin the transition into Th2 cells . Less is known about T follicular helper (Tfh) cell metabolism compared with other T cell subsets, but their lineage-defining transcription factor Bcl6 has been shown to suppress glycolysis potentiated by c-Myc and HIF-1 (Johnston et al, 2009;Nurieva et al, 2009;Oestreich et al, 2014).…”