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

TLDR

Stimulated CD4⁺ T lymphocytes differentiate into effector (Teff) or regulatory (Treg) subsets that perform distinct immunological functions. The study demonstrates that Teff and Treg rely on distinct metabolic programs to support their respective functions. Th1, Th2, and Th17 cells exhibit high Glut1 expression and glycolytic activity, whereas Treg cells display low Glut1 and elevated lipid oxidation. Glycolysis drives Teff expansion, as shown by increased Teff in Glut1 transgenic mice, while lipid oxidation promotes Treg, with AMP‑activated protein kinase activation reducing Glut1 and enhancing Treg generation in an asthma model, indicating that manipulating these metabolic pathways can control Treg and Teff development in inflammatory disease.

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.