Metabolic Pathways Underpinning Lymphocyte Differentiation and Responses in Health and Disease

Abstract

Lymphocytes mount protective immunity from infectious pathogens and from cancer. Their engagement by target antigens prompt activation, differentiation to effector cells and proliferation. These responses require energy that is generated by cellular metabolic processes, such as glycolysis and oxidative phosphorylation. Glycolysis occurs in the cytoplasm while oxidative phosphorylation occurs in the mitochondria. Energy in the form of adenosine triphosphate is generated from the uptake of glucose, amino acids and free fatty acids. Important recent evidence indicates that naïve and activated lymphocytes and functionally distinct subsets preferentially use different metabolic pathways for their energy needs. Thus, effector Th17 cells primarily use glycolysis to generate energy required for their activities. Memory T and B cells and regulatory T cells, in contrast, rely on mitochondrial metabolism for their energy requirements. Naïve T and B are in a quiescent state with small mitochondria. Extrinsic factors such as oxygen tension and intrinsic substrates can also influence the choice of metabolic pathways and functional flexibility. Studies of lymphocytes in disease states reveal alterations to choices of metabolic pathways from those in lymphocytes in healthy individuals. This article provides an overview of metabolic pathways required for energy generation during homeostasis and those induced during cellular differentiation and responses. Furthermore, we explore available evidence for altered metabolic pathway induction in some autoimmune diseases. A focus of the overview will be on helper T lymphocytes involved in chronic inflammation and those that regulate the immune response. The report alludes to the potential that targeting metabolic pathways could provide a strategy for the treatment of chronic diseases.