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Review
. 2016 May 19;17(6):618-25.
doi: 10.1038/ni.3466.

Immunometabolism of regulatory T cells

Ryan Newton  1 , Bhavana Priyadharshini  1 , Laurence A Turka  1
Affiliations
Review

Immunometabolism of regulatory T cells

Ryan Newton et al. Nat Immunol. .

Abstract

The bidirectional interaction between the immune system and whole-body metabolism has been well recognized for many years. Via effects on adipocytes and hepatocytes, immune cells can modulate whole-body metabolism (in metabolic syndromes such as type 2 diabetes and obesity) and, reciprocally, host nutrition and commensal-microbiota-derived metabolites modulate immunological homeostasis. Studies demonstrating the metabolic similarities of proliferating immune cells and cancer cells have helped give birth to the new field of immunometabolism, which focuses on how the cell-intrinsic metabolic properties of lymphocytes and macrophages can themselves dictate the fate and function of the cells and eventually shape an immune response. We focus on this aspect here, particularly as it relates to regulatory T cells.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1
Proposed model for the metabolic signatures of various Treg cell subsets. (a) Activated CD4+ T cells that differentiate into the Teff cell lineage (green) (TH1 or TH17 cells) are dependent mainly on carbon substrates such as glucose and glutamine for their anabolic metabolism. In contrast to that, pTreg cells that potentially mirror activated T cells that have differentiated into the iTreg cell lineage in vitro (purple) can rely on exogenous lipids and glucose-derived pyruvate that they can oxidize in the TCA cycle. Owing to their substantial dependence on FAO, iTreg cells generate increased amounts of ROS but are resistant to ROS-mediated damage, as they might be armed with antioxidant molecules to maintain their integrity. However, the metabolic properties of tTreg cells (blue) seem to resemble those of activated Teff cells to a greater degree than those of their pTreg cell counterparts in that they might be more dependent on glucose and glutamine than on fatty acids. (b) Tmem cells depend on glycolysis-driven lipogenesis and IL-7 receptor (IL-7R)-mediated expression of AQP9 for uptake of glycerol to generate cholesterol esters and triacylglycerols that can be hydrolyzed by LAL to mobilize free fatty acids (FA) to fuel FAO. Both tTreg cells and pTreg cells mirror certain metabolic properties of Tmem cells, in that they seem to rely on glucose-derived lipogenesis and FAO, respectively. Furthermore, the activation of co-inhibitory receptors such as CTLA-4 and PD-1 (which inhibit glycolysis while promoting FAO in activated T cells) might potentially have a role in influencing FAO in pTreg cells. In particular, activation of PD-1 has been shown to upregulate the enzyme ATGL (‘adipose triglyceride lipase’) that hydrolyzes intracellular triacylglycerol (TAG) into glycerol-3-phosphate and fatty acids for their utilization in FAO in activated T cells. Thus, although like Tmem cells, pTreg cells can depend on FAO, the means by which they obtain fatty acids might be different. Whether tTreg cells depend on FAO is yet to be determined.
Figure 2
Figure 2
Effects of metabolism on Foxp3 expression and the generation of Treg cells. There are various scenarios in which Treg cell signaling and metabolic pathways might integrate and potentially affect Foxp3 expression. One of the downstream effects of an enhancement in glycolytic metabolism is the production of metabolic intermediates that can also function as signaling molecules (1). For example, NAD+ and NADH might control Foxp3 stability via the activation of histone deacetylases such as SIRT proteins, which directly deacetylate Foxp3 in the nucleus and lead to its proteosomal degradation in the cytoplasm. Furthermore, the glycolytic enzyme enolase-1 can repress the FOXP3 splice variant containing exon 2 (E2) in human Treg cells, and its engagement in glycolysis serves as a mechanism by which glycolysis can control Foxp3 expression (2). Signaling molecules from glycolysis and mitochondrial metabolism (PEP and ROS) activate NFAT via Ca2+ mobilization during T cell activation, a process that could potentially affect Foxp3 expression in Treg cells as well (3). Activation of Foxo transcription factors and HIF-1α downstream of the PI(3)K-Akt-mTOR signaling pathway can reciprocally affect Foxp3 expression (4). Finally, the chromatin-modifying enzyme EZH2 that is crucial for the establishment of a repressive Treg cell gene program can be inhibited by specific microRNAs (such as miR-101 and miR-26a) under circumstances of glucose deprivation, which leads to Treg cell instability (5). ETC, electron-transport chain; PRC, polycomb repressive complex; IP3 and IP3R, inositol-1,3,4-trisphosphate and its receptor.
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