Nutrients and the microenvironment to feed a T cell army

Abstract

T cells have dramatic functional and proliferative shifts in the course of maintaining immune protection from pathogens and cancer. To support these changes, T cells undergo metabolic reprogramming upon stimulation and again after antigen clearance. Depending on the extrinsic cell signals, T cells can differentiate into functionally distinct subsets that utilize and require diverse metabolic programs. Effector T cells (Teff) enhance glucose and glutamine uptake, whereas regulatory T cells (Treg) do not rely on significant rates of glycolysis. The dependence of these subsets on specific metabolic programs makes T cells reliant on these signaling pathways and nutrients. Metabolic pathways, such as those regulated by mTOR and Myc, augment T cell glycolysis and glutaminolysis programs to promote T cell activity. These pathways respond to signals and control metabolism through both transcriptional or post-transcriptional mechanisms. Epigenetic modifications also play an important role by stabilizing the transcription factors that define subset specific reprogramming. In addition, circadian rhythm cycling may also influence energy use, immune surveillance, and function of T cells. In this review, we focus on the metabolic and nutrient requirements of T cells, and how canonical pathways of growth and metabolism regulate nutrients that are essential for T cell function.

Keywords: Circadian rhythms; Epigenetics; Glut1; Glutamine; T cell metabolism; mTOR.

Figure 1

Naïve T cells are predominantly oxidative and constantly monitor their environment for immune insult. Upon T cell receptor stimulation and co-stimulation by antigen presenting cells, T cells upregulate Myc expression and mTOR signaling, enhancing glycolysis and glutaminolysis (above). In tumor environment, some T cells exhibit high PD-1 expression and reduced activation. During the immune response, some cells will become memory T cells and return to naïve-like oxidative metabolism, whereas large populations of clonally selected T cells remain effector cells with high Myc and mTOR pathway signaling to respond to acute infection. In autoimmune settings, effector T cells react against self-antigens erroneously, enhancing effector responses that escape Treg suppression. Induced Treg (iTreg) are important in suppressing this peripheral autoreactivity.

Figure 2

The circadian clock exists in most somatic cells and is entrained by the Suprachiasmatic Nucleus in the brain via sunlight. This affects feeding behavior, sleep/wake cycles, circulating T cell counts, and more. In quiescent cells (right), cycling of metabolic sensor AMPK is coordinated with Clock:BMAL and PER1/PER2 expression, with concomitant cycling of glucose metabolism and potentially important in T cell maintenance and surveillance. Overexpression of Myc (left), increases REV-ERBα and REV-ERBβ expression to inhibit BMAL1 transcription and prevent circadian cycling. Myc expression induces glucose and glutamine metabolism and is required for T cell effector function.