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Your display name should be at least 2 characters long. At Kobo, we try to ensure that published reviews do not contain rude or profane language, spoilers, or any of our reviewer's personal information. As nothing is known regarding the metabolism of memory B cells, only memory T cells will be considered here.

Indeed, fatty acid oxidation is essential for rapid memory T cell responses Interestingly, these fatty acids are not taken up from the surrounding microenvironment, but rather memory T cells use glucose and glycolysis to generate citrate for de novo fatty acid synthesis and the generation and storage of triacylglycerides TAGs 44 , Nonetheless, this seemingly futile cycle of fatty acid synthesis and fatty acid oxidation is important for memory T cell survival 44 , This approach may be taken by memory T cells, for which long term survival is of utmost importance, as glucose levels are stringently controlled in the blood, making glucose a more dependable fuel source than fatty acids, whose levels can vary in different tissues.

Another advantage of this cycle of fatty acid synthesis and oxidation may be that it allows the cell to concurrently engage both glycolysis and OxPhos, thus maintaining the machinery required for rapid induction of metabolic flux through these pathways upon antigen recognition and so facilitating rapid functional responses. M2 macrophages have roles in tissue repair and secrete anti-inflammatory cytokines, growth factors, and factors involved in tissue remodeling Tregs and M2 macrophages oxidize both glucose and fatty acids in the mitochondria to sustain OxPhos 17 , 49 — It is likely that Tregs and M2 macrophages use glutamine metabolites to sustain cellular biosynthetic processes Fig.

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Indeed, M2 macrophages have increased glutamine metabolism when compared with M1 macrophages Additionally, given that M2 macrophages are professional scavengers of apoptotic debris, it is tempting to speculate that M2 macrophages sustain cellular biosynthesis using biomolecules scavenged from the surrounding microenvironment 48 , Controlling the longevity of immune cells is an important aspect of a healthy immune system. In contrast, it is crucial that upon resolution of a viral infection, the large population of CTL undergoes apoptosis as these effector T cells have the potential to cause significant immunopathology Therefore, CTL have a short lifespan of days to weeks.

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Similarly, differences in lifespan are apparent in different subsets of macrophages. M1 macrophages are short-lived and are a key component of the innate immune system that forms the first line of defense occurring within hours to days of an immunological challenge. In contrast, M2 macrophages are longer-lived as they have important roles within the resolution phase and in tissue repair and remodeling. Strikingly, the cellular metabolic signature of an immune cell corresponds to the longevity of the cell; aerobic glycolysis is characteristic of short-lived immune cells, whereas oxidative metabolism is characteristic of long-lived cells Fig.

It is perhaps unsurprising that OxPhos is important for longevity in immune cells given the importance of mitochondrial membrane potential in controlling the induction of apoptosis. Certainly, in activated DC, preserving OxPhos results in an increased cellular lifespan Moreover, in macrophages, switching cellular metabolism from glycolysis to oxidative metabolism promotes a shift from short-lived M1 macrophages to longer-lived M2 macrophages In addition, manipulating glycolytic versus oxidative metabolism impacts upon the formation of long-lived memory T cells; inhibiting glycolysis promotes memory T cell formation, whereas inhibiting fatty acid oxidation-dependent OxPhos represses memory T cell formation 55 , These reports are consistent with a number of other studies that also support the notion that promoting oxidative phosphorylation enhances cell survival and lifespan 57 — On the other hand, there are also numerous reports on a variety of cell types showing that manipulating glycolytic metabolism has profound impacts upon cellular viability 60 — Growth factors that promote elevated levels of cellular glycolysis also have the consequence of making that cell highly dependent on continued growth factor signaling and glycolysis for survival This provides an elegant mechanism for terminating effector T cell responses.

Cellular metabolism is crucial for facilitating immune cell functions, but in addition, there is emerging evidence that metabolic enzymes and regulators can also have a direct role in controlling immune cell functions. This mechanism provides a direct link between rates of glycolysis and the expression of important immunological effector molecules. Intriguingly, it appears that many other metabolic enzymes can bind to mRNA molecules including numerous glycolytic enzymes, Krebs cycle enzymes, and enzymes involved in other metabolic pathways Although the specific mRNA transcripts that these metabolic enzymes bind to still have to be identified, this study highlights the abundant potential for cellular metabolism to directly impact upon cellular functions.

Various metabolic regulators that evolved to control cellular metabolic pathways have since acquired roles in directly controlling immune cell function. AhR promotes Th17 differentiation, while inhibiting Treg differentiation, and is required for the production of the Th17 cytokines IL17 and IL22 74 — The transcription factor sterol regulatory element-binding protein Srebp , a central regulator fatty acid and cholesterol synthesis, has dual roles in controlling T cell metabolism and directly controlling genes required for immune function.

Therefore, there is growing evidence that multiple important regulators of cellular metabolism have additional functions in directly controlling immune responses. Distinct metabolic configurations will result in different levels of metabolites that can directly impact upon cellular function.

It has recently been shown that the glycolytic intermediate phosphoenolpyruvate is important in sustaining T cell receptor TCR signaling and T cell effector functions. Mitochondrial reactive oxygen species generated as a side product of OxPhos are also important for optimal TCR signal transduction.

T cells that cannot produce mitochondrial reactive oxygen species fail to activate nuclear NFAT, produce IL2, or engage in proliferative expansion Succinate can act as a signaling molecule that acts through the receptor SUCNR1 and can also be used as a substrate for the post-translational modification of proteins that is, succinylation Numerous metabolic enzymes are succinylated on lysine residues, but at present, it is not clear whether this modification impacts upon the regulation of immune responses Citrate levels are also elevated in M1 macrophages, and this metabolite is important for the production of various proinflammatory molecules: Cellular metabolites are also important substrates for various enzymes involved in the epigenetic control of gene expression via covalent modification of DNA and histones.

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Given that the distinct metabolic configurations that characterize immune cells result in different levels of these cellular metabolites, it follows that the epigenetic control of gene expression will differ in parallel with differences in metabolism. Jmjd3 has been shown to be of particular importance in controlling gene expression in LPS-stimulated macrophages Acetylation of histones is another post-translational modification that impacts on DNA structure and gene expression.

Acetylation of histones by histone acetyl transferases HATs requires acetyl-CoA, which is supplied via the export of mitochondrial citrate Fig. Indeed, there is evidence in yeast that the concentration of acetyl-CoA is important for histone acetylation Histone acetylation levels are also controlled by the rate of deacetylation. In fact, sirtuins can also deacetylate targets other than histones, which are important in immune regulation. Although there are numerous studies suggesting that cellular metabolism impacts upon epigenetic programming of immune cells to affect immune cell fate and function, the best evidence of this comes from a study of trained immunity in macrophages.

Therefore, it is clear that metabolites can impact directly on immune cell function, and it is likely that further examples of this will be revealed as the field of immunometabolism progresses. Links between cellular metabolism and epigenetic modifications. Methylation of DNA and histones is controlled by the rates of methylation and demethylation. The data now support an important role for cellular metabolism in controlling the function of immune cells. Given that metabolic regulators and pathways are acutely sensitive to external levels of nutrients, oxygen, and growth factors, cellular metabolism represents a means to relay information from the local microenvironment to modulate immune cell function accordingly.

Other nutrients are important for providing the substrates for enzymes that impact upon immune cell function. For example, methionine, which is an essential amino acid and so must be imported into the cell, is used to generate S -adenosylmethionine for epigenetic methylation of DNA and histones. Although most studies have focused on how activating immune receptors affect cellular metabolism, it is now becoming apparent that ligation of inhibitory receptors also alters metabolic pathways.

Recent research has demonstrated that ligation of the inhibitory receptors PD-1 and CTLA-4 expressed on human CD4 T cells has pronounced effects on cellular metabolism, inhibiting aerobic glycolysis, and in the case of PD-1, promoting fatty acid oxidation These data suggest that the inhibitory actions of these receptors may be mediated, at least in part, due to changes in cellular metabolism. The emerging data now argue that metabolism has duel roles in immune cells to facilitate requirements for energy and biosynthesis and to directly regulate immune cell functions.

There are likely to be numerous opportunities for novel therapeutic strategies that modulate this metabolic regulatory axis. The authors declare that they have no conflicts of interest with the contents of this article.

You'll be in good company. Journal of Lipid Research. Previous Section Next Section. Inflammatory Microenvironments Most normal tissue is well vascularized and replete with nutrients and oxygen.

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Dynamic Changes in Cellular Function Immune activation is accompanied by substantial changes in cellular activities, such as those accompanying T cell activation. Aerobic Glycolysis in Activated Lymphocytes Upon stimulation through antigen or cytokine receptors, lymphocytes increase the rates of both glycolysis and OxPhos Fig.

Aerobic Glycolysis in Myeloid Cells Unlike lymphocytes, mature myeloid cells tend to be non-proliferative and so have substantially different metabolic requirements. Oxidative Metabolism Supports Immune Cell Longevity Controlling the longevity of immune cells is an important aspect of a healthy immune system. Metabolic Enzymes or Regulators Controlling Immune Cell Function Cellular metabolism is crucial for facilitating immune cell functions, but in addition, there is emerging evidence that metabolic enzymes and regulators can also have a direct role in controlling immune cell functions.

Metabolites Controlling Immune Cell Function Distinct metabolic configurations will result in different levels of metabolites that can directly impact upon cellular function. Immune Metabolism Relays External Signals to Regulate Immune Cell Function The data now support an important role for cellular metabolism in controlling the function of immune cells.

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