Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets

Abstract

Stimulated CD4+ T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4+ T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.

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

“…Importantly, T Reg cells do not use glycolysis after stimulation, largely owing to their selective blockade of PI3K-AKT activation, preventing GLUT1 upregulation. Instead, T Reg cells heavily rely on fatty acid oxidation to feed the tricarboxylic acid cycle and generate energy through oxidative phosphorylation [95][96][97] . Thus, PTEN deficiency in T Reg cells may drive loss of FOXP3 expression and effector cytokine production by enforcing glycolytic metabolism 79,80 .…”

“…AMPK deficiency also releases mTORC1 to activate HIF1α and promote the expression of genes that favour glyco lysis 109 , and aero bic glycolysis itself promotes the production of inflammatory cytokines 110 . Enforced activation of AMPK with the agonist metformin broadly blocks effector T cell function but promotes T Reg cell induction and function 96 . Activated AMPK blocks fatty acid biosynthesis by inhibiting acetyl-CoA carboxylase 1 (ACC1), and deletion of ACC1 in T cells favours T Reg cell polarization at the expense of T H 17 cell polarization 96,111 .…”

“…Enforced activation of AMPK with the agonist metformin broadly blocks effector T cell function but promotes T Reg cell induction and function 96 . Activated AMPK blocks fatty acid biosynthesis by inhibiting acetyl-CoA carboxylase 1 (ACC1), and deletion of ACC1 in T cells favours T Reg cell polarization at the expense of T H 17 cell polarization 96,111 . Thus, T cell plasticity can be controlled by the metabolic programmes of the cell that respond dynamically to fluctuations in the nutrients, oxygen levels and energy sources present in the environment.…”

Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation

“…These processes require energy expenditure and biosynthesis (2,3) and T-cell stimulation triggers a rapid increase in cellular metabolism to support activation and differentiation pathways (4,5). We have shown that specific metabolic demands differ between CD4 + T-cell subsets, as Teff cells (Th1, Th2, and Th17) are dependent upon glycolysis, while Tregs use and require lipid oxidation (6). Contributing to these metabolic phenotypes, the phosphatidyl-inositol 3-kinase (PI3K)/Akt mammalian target of rapamycin (mTOR) and hypoxia-inducible factor 1α (HIF1α) signaling pathways promote glycolysis and cell-surface trafficking of the glucose transporter Glut1, while diminishing lipid oxidation (7)(8)(9).…”

Cutting Edge: Increased Autoimmunity Risk in Glycogen Storage Disease Type 1b Is Associated with a Reduced Engagement of Glycolysis in T Cells and an Impaired Regulatory T Cell Function

“…It has been shown that different cellular metabolic pathways are able to induce effector or regulatory responses, because distinct metabolic programs are required for the commitment of effector or Treg responses (13). In this context, although Tregs generated in vitro in the presence of TGF-b were shown to rely mainly on lipid oxidation (14), recent reports have also shown a major role for glycolysis in the induction and suppressive function of human and mouse Tregs (15,16), given the capacity of the glycolytic enzyme enolase-1 to control the expression of specific FOXP3 splicing variants in human Tregs (16). Interestingly, in human autoimmunity (i.e., multiple sclerosis and type 1 diabetes), an impaired engagement of glycolysis upon suboptimal TCR stimulation of CD4 + CD25 2 conventional T cells (Tconvs) has been observed, and this is associated with a reduced suppressive function of Tregs (16).…”