GLUT1-mediated glucose import in B cells is critical for anaplerotic balance and humoral immunity
Glucose uptake increases during B cell activation and plasma cell differentiation. However, conflicting findings regarding the role of glucose at different stages of B cell activation prevents establishing a clear metabolic profile. To determine whether glucose is required for establishing humoral immunity, we deleted the glucose transporter type 1 (GLUT1)-encoding gene (Slc2a1fl/fl) in mature B cells by CD23-mediated Cre expression (GLUT1-cKO). While B cell development was normal, germinal center B cell and antibody-secreting cell numbers (ASCs) were severely reduced in GLUT1-cKO mice. In addition, these mice could hardly mount antigen-specific antibody titers after vaccination. Activation of GLUT1-deficient B cells in vitro was impaired and the remaining plasmablasts abolished glycolysis, relying on mitochondrial activity and fatty acid metabolism. Metabolomics combined with genome-wide transcriptome analysis revealed a dramatically altered anaplerotic balance in GLUT1-deficient ASCs. Although the cells attempt to compensate for glucose deprivation by increasing their mitochondrial mass and the expression of genes responsible for glycolysis, the tricarboxylic acid cycle and the hexosamine synthesis pathways, they lack both the necessary metabolites for energy production and functional mitochondrial respiration. Consequently, protein synthesis was limited in GLUT1-deficient ASCs. Thus, we identified GLUT1 as a critical metabolic player defining the germinal center response and humoral immunity. Overall design: Comparative gene expression profiling analysis of RNA-seq data for splenic plasma cells from CD23cre(+/-);Slc2a1(fl/fl) and CD23cre(+/-);Slc2a1(wt/wt) mice