Glucose metabolism regulates T cell activation, differentiation, and functions

Abstract

The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The "Warburg effect" originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.

Keywords: HIF-1α; HIV; PI3K; glucose transporter 1; immune activation; inflammation; mTOR; metabolism.

Figure 1

Glucose metabolic programs regulate glucose uptake, activation, and differentiation of CD4+ T cells. (A) Mitogenic stimulation or engagement of the TCR complex activates the phosphoinositide 3-kinase (PI3K)-gamma (PI3Kg) subunit in CD4+ T cells. Activation of the PI3Kγ in CD4+ T cells promote Glut1 trafficking from the cytoplasm to the cell membrane and increases glucose uptake to sustain activation. (B) Upon activation, T cells increase glucose uptake through Glut1, which facilitate increased oxidative phosphorylation and glycolysis to sustain cell growth and proliferation. (C) Unique metabolic changes upon differentiation of T cells toward different subsets, regulated by various transcription factors and signaling pathways.