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. Author manuscript; available in PMC: 2016 Aug 31.
Published in final edited form as: Nat Immunol. 2016 May 19;17(6):618–625. doi: 10.1038/ni.3466

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.