Sugar or Fat?-Metabolic Requirements for Immunity to Viral Infections

Abstract

The realization that an intricate link exists between the metabolic state of immune cells and the nature of the elicited immune responses has brought a dramatic evolution to the field of immunology. We will focus on how metabolic reprogramming through the use of glycolysis and fatty-acid oxidation (sugar or fat) regulates the capacity of immune cells to mount robust and effective immune responses. We will also discuss how fine-tuning sugar and fat metabolism may be exploited as a novel immunotherapeutic strategy to fight viral infections or improve vaccine efficacy.

Keywords: HIV; T cells; glycolysis; immunometabolism; mTOR; viral infection.

Figure 1

Metabolic requirements of naïve CD8⁺ T cells (Tn). Glucose and fatty acids are major nutrient sources for immune cells and are metabolized predominantly via OXPHOS and FAO in naïve T cells (Tn). Glycolytic enzymes like GAPDH when not involved in glycolysis may engage the 3′-UTR of effector cytokines like IFN-γ and IL-2 and suppress their production. CPT1a, carnitine palmitoyltransferase 1A; FAs, fatty acids; FAO, fatty-acid oxidation; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; G-6-PI, glucose-6-phosphate isomerase; IFN-γ, interferon-γ; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle; 3′UTR, three prime untranslated region.

Figure 2

Metabolic requirements of effector CD8⁺ T cells (Teff). Early generation of effector cells requires a metabolic reprogramming from OXPHOS and FAO toward aerobic glycolysis with increased OXPHOS driven by FAO in late effector stage. A hallmark of aerobic glycolysis is elevated aerobic glycolysis and secretion of lactate. PPP intermediates are elevated to support synthesis of nucleotides, proteins and lipids for cell growth, proliferation, and effector responses. In activated effector cells, the HBP may utilize F-6-P to form glucosamine-6-phosphate by glutamine-fructose-6-phosphate transaminase in the presence of glutamine. This is a key step in the production of UDP-GlcNAc, a substrate for protein glycosylation. GAPDH a key glycolytic enzyme may disengage the 3′-UTR of effector cytokines to perform its metabolic role, thereby inducing cytokine production. Activated effector cells also increase glutamine uptake which generates α-KG via anaplerosis. This α-KG supports the TCA cycle under condition of limited pyruvate and acetyl-CoA. α-KG may also directly activate mTOR. CPT1a, carnitine palmitoyltransferase 1A; FAs, fatty acids; FAO, fatty-acid oxidation; F-6-P, fructose-6-phosphate; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HBP, hexosamine biosynthetic pathway; α-KG, α-ketoglutarate; OXPHOS, oxidative phosphorylation; PPP, pentose phosphate pathway; mTOR, mechanistic target of rapamycin; TCA, tricarboxylic acid cycle; UDP-GlcNAc, uridine diphosphate N-acetyl glucosamine; 3′-UTR, three prime untranslated region.

Figure 3

Metabolic requirements of memory CD8⁺ T cells (Tm). Increased mitochondrial density and a metabolic configuration toward OXPHOS and FAO allows Tm cells to concurrently engage in both glycolysis and OXPHOS for rapid metabolic flux upon antigen recognition to facilitate a rapid and robust functional response. GDCs are used for FA synthesis in the ER, which can undergo FAO to generate acetyl-CoA to fuel the TCA cycle to generate ATP. CPT1a, carnitine palmitoyltransferase 1A; ER, endoplasmic reticulum; FAs, fatty acids; FAO, fatty-acid oxidation; GDCs, glucose-derived carbons; OXPHOS, oxidative phosphorylation; TCA, tricarboxylic acid cycle.

Figure 4

Metabolic reprogramming playing a critical role in governing the generation and function of CD8⁺ effector (Teff) and memory cells (Tm). This figure summarizes some of the major pathways and molecular players involved at each stage of CD8⁺ T cell differentiation following viral infections and how these pathways influence the magnitude of the Teff and Tm responses. Metabolic pathways, key enzymes, transcription factors, or intervention strategies that are decreased or that would hamper the development of Tm are shown in red, while those that enhance Tm responses are shown in green.