T-cell metabolism governing activation, proliferation and differentiation; a modular view

Abstract

T lymphocytes are a critical component of the adaptive immune system mediating protection against infection and malignancy, but also implicated in many immune pathologies. Upon recognition of specific antigens T cells clonally expand, traffic to inflamed sites and acquire effector functions, such as the capacity to kill infected and malignantly transformed cells and secrete cytokines to coordinate the immune response. These processes have significant bioenergetic and biosynthetic demands, which are met by dynamic changes in T-cell metabolism, specifically increases in glucose uptake and metabolism; mitochondrial function; amino acid uptake, and cholesterol and lipid synthesis. These metabolic changes are coordinate by key cellular kinases and transcription factors. Dysregulated T-cell metabolism is associated with impaired immunity in chronic infection and cancer and conversely with excessive T-cell activity in autoimmune and inflammatory pathologies. Here we review the key aspects of T-cell metabolism relevant to their immune function, and discuss evidence for the potential to therapeutically modulate T-cell metabolism in disease.

Keywords: T cells; cell activation; cell differentiation; cell proliferation; inflammation.

Figure 1

Glycolysis pathway. Glucose is converted to pyruvate through sequential enzymatic reactions occurring in the cytosol. Intermediates of this process can be further metabolised to yield precursors for synthesis of nucleic acids, lipids and amino acids, which are critically required for T‐cell clonal expansion. Pyruvate can be either oxidized in the mitochondria to drive the tricarboxylic acid (TCA) cycle; oxidative phosphorylation (OXPHOS) and ATP generation, or reduced to lactate and excreted. The latter is favoured in proliferating T cells to maintain high rates of glycolysis and precursor molecule generation.

Figure 2

The tricarboxylic acid (TCA) cycle. Glucose‐derived pyruvate, once converted in the mitochondria to acetyl‐CoA by pyruvate dehydrogenase (PDH), enters the TCA cycle to yield biosynthetic intermediates (citrate, α‐ketoglutarate and oxaloacetate) and reduced electron carriers (NADH and FADH ₂) that drive oxidative phosphorylation (OXPHOS) by the electron transport chain. Fatty acids and glutamine can also fuel the TCA cycle, following fatty acid oxidation and glutaminolysis, respectively.

Figure 3

Oxidative phosphorylation (OXPHOS) by the electron transport chain (ETC). The ETC consists of five multi‐subunit complexes, which are located within the inner mitochondrial membrane. Complexes I and II accept electrons from reduced NADH and FADH2, respectively, and pass them, via Coenzyme Q (Q), to Complex III and subsequently via cytochrome c (C) to complex IV. Complex IV finally transfers the electrons to molecular oxygen as final electron acceptor to reduce oxygen to water. The redox energy generated through the electron transfer can be used by complexes I, III and IV to pump protons (H⁺) across the mitochondrial inner membrane into the inter‐membrane space, building up an electrochemical proton gradient across the mitochondrial inner membrane. This membrane potential (Δϕm) can then be used by Complex V (ATP‐Synthase) to generate adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and phosphate.