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. 2017 May 16;46(5):714-729.
doi: 10.1016/j.immuni.2017.04.016.

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

Free PMC article

Metabolic and Epigenetic Coordination of T Cell and Macrophage Immunity

Anthony T Phan et al. Immunity. .
Free PMC article


Recognition of pathogens by innate and adaptive immune cells instructs rapid alterations of cellular processes to promote effective resolution of infection. To accommodate increased bioenergetic and biosynthetic demands, metabolic pathways are harnessed to maximize proliferation and effector molecule production. In parallel, activation initiates context-specific gene-expression programs that drive effector functions and cell fates that correlate with changes in epigenetic landscapes. Many chromatin- and DNA-modifying enzymes make use of substrates and cofactors that are intermediates of metabolic pathways, providing potential cross talk between metabolism and epigenetic regulation of gene expression. In this review, we discuss recent studies of T cells and macrophages supporting a role for metabolic activity in integrating environmental signals with activation-induced gene-expression programs through modulation of the epigenome and speculate as to how this may influence context-specific macrophage and T cell responses to infection.


Figure 1
Figure 1. Regulation of epigenetic state and metabolic pathway usage in macrophages and T cells following activation
A Activation of immune cells results in substantial remodeling of epigenetic landscapes. Genes associated with the naive state are repressed and effector genes become active through deposition of repressive marks (i.e. H3K9me3 and H3K27me3) and activating marks at promoters and enhancers (i.e. H3K27ac and H3K4me1). Diversity in epigenetic landscapes correlates with diversity in responses and plays a role in specifying differentiation. B Classical activation of macrophages elicits increased glycolytic metabolism and reduced reliance on mitochondrial respiration. These gross alterations in metabolic pathway usage underlie specific changes in the abundance of several metabolites. In particular, increased glycolytic metabolism drives production of lactate and supports a pool of acetyl-CoA by slowing the TCA cycle resulting in a buildup of citrate that can be converted to acetyl-CoA as well. Reduced flux through the TCA cycle, also reduces the production of 2-oxoglutarate and increases the production of itaconate. Alternatively, TLR stimulation of macrophages along with IL-4 reduces glycolytic metabolism and drives increased mitochondrial respiration and oxidative phosphorylation. C TCR and co-receptor stimulation of Th1, Th2, Th17, Tr1, and CD8+ T cells drives a general increase in both glycolytic metabolism and mitochondrial metabolism as measured by extracellular flux analysis. Glucose transport is increased substantially to facilitate glycolytic metabolism and mitochondrial mass increases as well. Tregs on the other hand do not exhibit as dramatic an increase in glucose uptake and glycolytic metabolism, but increase reliance on oxidative phosphorylation and FAO. Biosynthetic pathways are engaged to fuel proliferation, in particular serine-driven folate metabolism, a branch of one-carbon metabolism, that promotes nucleotide synthesis. Extensive characterization of metabolic changes that occur during memory CD8+ T cell differentiation show that in general memory CD8+ T cells exhibit reduced metabolic activity, glycolytic and mitochondrial, with metabolic heterogeneity exhibited within the memory pool. Tcm maintain high mitochondrial mass, substantially increased SRC fueled by increased FAO. Tem maintain lower levels of SRC and can be supported by high levels of glycolytic metabolism. Examination of Trm metabolism show that skin Trm uniquely rely on high levels of fatty acid import to fuel FAO and SRC.
Figure 2
Figure 2. Pathogen recognition initiates induction of biosynthetic and energetic pathways impacting “writers” and “erasers” of the epigenetic code
Recognition of pathogen by immune cells initiates a genetic program that promotes use of numerous metabolic pathways for biogenesis (i.e. nucleotide synthesis) and energy production (i.e. glycolysis, TCA cycle). Metabolites involved in glycolysis (teal), TCA cycle (orange), and one-carbon metabolism (light-green) can play critical roles as substrates such as acetyl-CoA and SAM, for histone acetylation and methylation respectively, or cofactors such as 2-oxoglutarate and NAD+, for demethylation of DNA and histone deacetylation respectively. Epigenetic enzymes (blue) catalyze the addition (HAT, HMT or DNMT) and removal (HDAC, JHDM, or TET) of epigenetic marks and can be impacted by multiple metabolic pathways. Metabolites shown to be controlled by pathways relevant in T cells or macrophages (bold) are critical for energy production (i.e. lactate, acetyl-CoA) and proliferation (i.e. serine). Flexibility in metabolic pathway usage is reflected by the small network depicted here; for example, 3-phosphoglcerate can be converted to serine for use in one-carbon metabolism. Clear links between activity of epigenome modifying enzymes and metabolites relevant in T cells and macrophages that will impact the epigenetic landscape of activated cells can be drawn.
Figure 3
Figure 3. Effect of extrinsic metabolism/metabolites on epigenome of macrophages and T cells
Activated immune cells initiate rapid metabolic and epigenetic changes that are responsive to additional stimuli encountered in peripheral tissues. Migration to peripheral tissues submit immune cells to additional challenges such as changes in nutrient availability, tissue-specific signals, as well as alter the metabolic pathways that are utilized by the cell in situ. Cells that enter the gut microenvironment must contend with microbiome derived metabolites, such as butyrate, that has been shown to inhibit HDACs and modulate macrophage and T cell differentiation and function. Similarly, immune cells that infiltrate tumors encounter a challenging environment with increased competition for glucose, higher concentrations of lactate, and reduced oxygen levels. Reduced glucose availability could impair glycolytic metabolism reduce acetyl-CoA levels and inhibit the acetylation of histones necessary for gene expression. Increased lactate concentrations may inhibit HDAC activity further dysregulating the epigenetic landscapes of tumor-infiltrating immune cells. These examples highlight the possible effects of extrinsic signals on epigenetic enzymes and support a role for metabolites as integrators of cell-intrinsic and –extrinsic signals for the modulation of gene expression.

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