Fueling immunity: insights into metabolism and lymphocyte function

Abstract

Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting. An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked. However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear. Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming. In this Review, we highlight emerging concepts regarding metabolic reprogramming in proliferating cells and discuss their potential impact on T cell fate and function.

Fig. 1. T cell metabolism changes over the course of an immune response

T cells display distinct metabolic profiles depending on their state of activation. Naïve T cells (T_N, blue) are metabolically quiescent; they adopt a basal level of nutrient uptake and use OXPHOS as their primary pathway of ATP production. Upon immune challenge, T_EFF (green) cells shift to a state of metabolic activation characterized by increased nutrient uptake, elevated glycolytic and glutaminolytic metabolism, biomass accumulation, and reduced mitochondrial SRC. T_EFF cells preferentially use glycolysis over OXPHOS for ATP production. Transition to the T_M (orange) stage is characterized by a quiescent metabolism, with increased reliance on FAO to fuel OXPHOS. Mitochondrial mass and SRC are elevated in T_M cells, suggesting that these cells are metabolically primed to respond upon reinfection.

Fig. 2. Metabolic pathways that support cell growth and proliferation

Glycolysis and the TCA cycle are two separate yet connected biochemical pathways that function to generate ATP as well as metabolic precursors for biosynthesis. Glucose is broken down to pyruvate by glycolysis (orange); pyruvate can be further oxidized by the TCA cycle in the mitochondrion. Glycolytic intermediates can be used to generate other metabolites required for growth and proliferation. Glucose 6-phosphate and 3PG produced from glycolysis are metabolized in the PPP (green) and the SBP (blue), respectively, providing important precursors for nucleotide biosynthesis. Similarly, acetyl-CoA, generated from glucose-derived citrate in the TCA cycle, can be used for lipid biosynthesis. OAA, produced as part of the TCA cycle, can be used to generate aspartate, another precursor for nucleotide synthesis. An alternate source of carbon for the TCA cycle occurs via glutaminolysis (purple); in this pathway, glutamine is converted to glutamate and then to α-KG, which joins the TCA cycle. Glutamine is also a precursor for amino acid and nucleotide biosynthesis. Key enzymes in these pathways are PHGDH; PKM2; LDHA, lactate dehydrogenase; PDH; GLS, glutaminase; SDH, succinate dehydrogenase; and FH.

Fig. 3. Serine biosynthesis and reductive carboxylation are anabolic pathways that support cell proliferation

(A) The SBP converts glucose-derived 3PG into serine and glycine, which are precursors for lipid and nucleotide biosynthesis. Serine is also involved in folate-mediated one carbon metabolism by acting as a methyl group donor for THF to methylene-THF conversion. Key enzymes in this pathway are PHGDH, PSAT, and SHMT. (B) Reductive carboxylation is an alternate pathway of glutamine metabolism in which glutamine-derived α-KG is converted to citrate through reverse TCA cycle flux. Under conditions of hypoxia or mitochondrial dysfunction (right), isocitrate dehydrogenase (IDH1 in cytosol, IDH2 in mitochondria) uses CO₂ and NADPH to convert α-KG into isocitrate. Citrate produced downstream of this reaction is converted into cytosolic acetyl-CoA without passing through the conventional clockwise steps of the TCA cycle. Acetyl-CoA generated by this pathway can function as a precursor for fatty acid synthesis. α-KGDH, α–KG dehydrogenase.

Fig. 4. Metabolites can influence signal transduction

(A) The AMPK pathway is influenced by adenylate concentration. AMPKα is activated by phosphorylation on Thr¹⁷² of its activation loop by the kinases LKB1, TAK1, or CaMKKβ. LKB1 promotes enhanced AMPK phosphorylation under a high AMP:ATP ratio. One biological output of AMPK activity is the inhibition of mRNA translation under low-energy conditions through inhibition of mTORC1 activity. (B) α-KG– dependent enzymes (in yellow) are a class of enzymes regulated by TCA cycle intermediates that require molecular oxygen (O₂) and α-KG for their enzymatic activity. Oxygen, α-KG, ascorbate, and iron (green) are positive regulators of these enzymes, whereas the TCA cycle intermediates fumarate and succinate (blue) antagonize their reactions. PHDs destabilize HIF-1α protein, resulting in decreased expression of HIF-1α targets and a reduction in glycolysis. TET2 hydroxylates 5-methylcytosine residues to promote DNA demethylation, whereas JmjC promotes demethylation of trimethylated histones in chromatin.

Fig. 5. Bifunctional metabolic enzymes connect metabolism and gene regulation

Metabolic enzymes can moonlight as RNA binding proteins and regulate the translation of specific target mRNAs. The RNA binding function of enzymes can be influenced by interactions with intermediary metabolites and cofactors, leading to posttranscriptional regulation of protein expression. Posttranslational modification of metabolic enzymes could influence their RNA binding function directly or by altering the enzyme’s subcellular location. Changes in metabolic conditions, such as bioenergetic demand, hypoxia, stress, and substrate availability, may affect the consequences of the REM interactions. The overall balance of the network between RNA, enzymes, and metabolites can potentially influence T cell fate and function.

Fig. 6. T cells must display metabolic plasticity to adapt to changes in nutrient and oxygen availability in vivo

T_EFF (green) cells must adapt to varying oxygen and nutrient levels depending on environmental context. Lymphoid organs (middle) are considered to be nutrient- and oxygen-replete areas, whereas sites of inflammation (left) and the tumor micro-environment (right) contain hypoxic areas with fluctuations in nutrient availability. At sites of inflammation, nutrient and oxygen availability may become limited because of the metabolic activity of cells at the site of inflammation, necrosis of infected cells, and oxygen consumption by neutrophils. Tumor microenvironments can be highly hypoxic resulting from insufficient vascularization. Additionally, T cells must compete with tumor cells for nutrients such as glucose.