Metabolic regulation of regulatory T cell development and function

Abstract

It is now well established that the effector T cell (Teff) response is regulated by a series of metabolic switches. Quiescent T cells predominantly require adenosine triphosphate-generating processes, whereas proliferating Teff require high metabolic flux through growth-promoting pathways, such as glycolysis. Pathways that control metabolism and immune cell function are intimately linked, and changes in cell metabolism at both the cell and system levels have been shown to enhance or suppress specific T cell effector functions. Furthermore, functionally distinct T cell subsets require distinct energetic and biosynthetic pathways to support their specific functional needs. In particular, naturally occurring regulatory T cells (Treg) are characterized by a unique metabolic signature distinct to that of conventional Teff cells. We here briefly review the signaling pathways that control Treg metabolism and how this metabolic phenotype integrates their differentiation and function. Ultimately, these metabolic features may provide new opportunities for the therapeutic modulation of unwanted immune responses.

Keywords: T cell differentiation; T cell function; mTOR pathway; metabolism; regulatory T cells.

Figure 1

mTORC1 is a key regulator of T_reg and T_eff activation and differentiation. Signaling through the TCR is accompanied by cytokine signals from IL-2, IL-7, and leptin as well as co-stimulation via CD28. Together, these signals cause increased glycolysis through the induction of PI3K-dependent activation of Akt, which in turn increases glucose transport via the upregulation of Glut1 on the T cell surface. Activated pAkt increases the rate of protein synthesis via activation of mTORC1. Activated mTORC1 activates HIF1α, regulates lipid metabolism and glycolysis.

Figure 2

The level of mTORC1 activity and glycolysis is important for differentiation of T cell subsets. mTORC1 integrates nutrient sensing and signaling pathways to match the energy requirements of activated T cells. Th1, Th2, and Th17 cells require high levels of glycolysis that is mediated by high mTORC1 activity, whereas T_reg differentiation requires variable mTorc activity, reduced glycolysis, and lipid oxidation.