The unusual metabolism of germinal center B cells

Abstract

Germinal center B cells (GCBCs) rely on oxidative phosphorylation to produce ATP. In contrast to clonally expanding T cells and pre-GCBCs, GCBCs are not dependent on aerobic glycolysis for ATP production. Ex vivo GCBCs utilize fatty acids for ATP production. GCBCs divert a significant amount of glucose away from glycolysis into biosynthetic pathways. The expression of c-MYC correlates with the expression of PKM2, which may be a key step in redirecting glucose. In GCBCs, glucose is used for the pentose phosphate pathway (PPP) and one-carbon metabolism to synthesize nucleotides, glutathione, S-adenosyl methionine, NADPH, and amino acids. GCBCs increase exogenous amino acid uptake and are sensitive to glutamine and asparagine deprivation. The GC response is sensitive to nutrient availability, with evidence that pathogens can inhibit GCs by quenching extracellular nutrients. Germinal centers (GCs) are responsible for generating high-affinity, long-lived B cell responses which are fundamental for effective immune responses and vaccine efficacy. Some pathogens can evade immune clearance by inhibiting the GC response. Understanding which metabolic changes support GC B cells to undergo cycles of positive selection and proliferation may be crucial for targeted therapies to improve vaccine efficacy and mitigate disease-associated GC dysfunction. In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways. In the germinal center (GC), B cells undergo rounds of somatic hypermutation (SHM), proliferation, and positive selection to develop into high-affinity, long-lived plasma cells and memory B cells. It is well established that, upon activation, B cells significantly alter their metabolism, but until recently little was understood about their metabolism within the GC. In this review we discuss novel in vivo models in which GC B cell (GCBC) metabolism is disrupted; these have greatly increased our understanding of B cell metabolic phenotype. GCBCs are unusual in that, unlike almost all other rapidly proliferating immune cells, they use little glycolysis but prefer fatty acid oxidation (FAO) to fuel ATP synthesis, whilst preferentially utilizing glucose and amino acids as carbon and nitrogen sources for biosynthetic pathways.

Topics & Concepts