Matched and mismatched metabolic fuels in lymphocyte function

Abstract

Immunological function requires metabolic support to suit the needs of lymphocytes at a variety of distinct differentiation and activation states. It is now evident that the signaling pathways that drive lymphocyte survival and activity can directly control cellular metabolism. This linkage provides a mechanism by which activation and specific signaling pathways provide a supply of appropriate and required nutrients to support cell functions in a pro-active supply rather than consumption-based metabolic model. In this way, the metabolism and fuel choices of lymphocytes are guided to specifically match the anticipated needs. If the fuel choice or metabolic pathways of lymphocytes are dysregulated, however, metabolic checkpoints can become activated to disrupt immunological function. These changes are now shown in several immunological diseases and may open new opportunities to selectively enhance or suppress specific immune functions through targeting of glucose, lipid, or amino acid metabolism.

Figure 1. B cell metabolism in activation

A naïve B cell utilizes a variety of fuels for energy, including glucose (Glc), amino acids (aac) and fatty acids (FA). These fuels are metabolized in the mitochondria to provide energy for survival and migration. Upon stimulation, a B cell increases the uptake of amino acids, primarily glutamine, and glucose. These are used to provide biosynthetic precursors for cell division. Instead of being oxidized in the mitochondria, glucose is converted to lactate in the cytoplasm in a process known as aerobic glycolysis. Fatty acid oxidation is decreased and the lipids are instead used to build new membranes. Once a B cell differentiates into a plasma cell, the metabolic phenotype becomes more about generating ATP energy. The cell metabolizes glutamine for energy and the rate of glycolysis is decreased.

Figure 2. Metabolic checkpoints and apoptosis

Activation, metabolism, and cell death are interconnected. Upon stimulation, lymphocytes activate pro-survival and proliferative pathways in conjunction with an increase in glucose metabolism. Under low glucose conditions, the pathways that drive activation and proliferation are inhibited, and if the signal persists, pro-apoptotic genes will be induced. On the other hand, under low or no stimuli, metabolic genes are downregulated, leading cells to a low metabolic state and eventually anergy. In both cases, the metabolic state of the cell can influence cell fate. For instance, low glucose will lead to an insufficient response, while a high glucose environment may cause an excessive response under low stimulation.