Cellular Metabolism in B cells: Roles of AMP-activated Protein Kinase, Glutamine, and Glucose Metabolism in Humoral Immunity

Abstract

Metabolism underpins many processes in cellular biology. Many diseases including cancer often involve aberrant metabolic pathways with altered reliance on metabolites, metabolic enzymes, or metabolic regulators. B lymphocytes are a good model for studying metabolism because they have multiple differentiation states with dynamic energy and biosynthetic requirements. Metabolic sensor and orchestrator of a plethora of metabolic programs, AMP-activated protein kinase (AMPK), is critical for metabolic adaptation to stressful nutrient-limiting conditions in multiple cell types and settings. In my thesis work, I show that AMPK is critical for maintaining the memory B cell population by promoting mitochondria homeostasis. Specifically, AMPK supports mitophagy and mitigates mitochondria-derived reactive oxygen species and lipid peroxidation in memory B cells. In the antibody-secreting cell population, AMPK fine-tunes immunoglobulin synthesis through regulation of mTORC1. AMPK has been shown to influence both glutamine and glucose metabolism, both critical fuels for B cell activation, differentiation, and antibody synthesis. In my thesis work, I show that glucose import and glutamine metabolism synergistically influence antibody production. Understanding critical metabolic pathways of the B lineage may lead to therapeutic targets for effective vaccine development and immune pathologies.