Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis

Abstract

Germinal center B cells (GCBCs) are critical for generating long-lived humoral immunity. How GCBCs meet the energetic challenge of rapid proliferation is poorly understood. Dividing lymphocytes typically rely on aerobic glycolysis over oxidative phosphorylation for energy. Here we report that GCBCs are exceptional among proliferating B and T cells as they actively oxidize fatty acids (FAs) and conduct minimal glycolysis. In vitro, GCBCs had a very low glycolytic extracellular acidification (ECAR) but consumed oxygen in response to FAs. [ 13 C 6 ]-glucose feeding revealed that GCBCs generate significantly less phosphorylated glucose and little lactate. Further, GCBCs did not metabolize glucose into TCA cycle intermediates. Conversely, [ 13 C 16 ]-palmitic acid labeling demonstrated that GCBCs generate most of their acetyl-CoA and acetylcarnitine from FAs. FA oxidation (FAO) was functionally important, as drug-mediated and genetic dampening of FAO resulted in a selective reduction GCBCs. Hence, GCBCs appear to uncouple rapid proliferation from aerobic glycolysis.

Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity

“…SCD, which catalyzes the generation of endogenous OA, critically contributes to B cell development and activation. These observations are consistent with a recent study that GC B cells preferentially utilize FAO rather than glycolysis 14 . However, our results indicate that all FAs are not created equal for B cells.…”

“…FAs can be utilized to fuel mitochondrial oxidative phosphorylation (OXPHOS) and to provide energy, but it is unclear how different FAs contribute to B cell metabolism. Indeed, the inhibitor etomoxir, which blocks carnitine palmitoyltransferase I (CPT1)-mediated FA import to mitochondrial, reduced B cell class switch, and negated the effects of OA treatment at 40 µM, a dose selective to CPT1 inhibition 14 (Fig. 3A).…”

“…A recent study showed that germinal center (GC) B cells mainly utilize FA oxidation, rather than glycolysis, to meet their energetic need, highlighting the importance of FA availability for humoral immunity 14 . While FAs are known to contribute to energy metabolism through boxidation, most studies in immunometabolism do not distinguish different FAs.…”

Immunometabolism: From basic mechanisms to translation

“…45 Germinal centers also provide a dynamic microenvironment which may be hypoxic to drive glycolysis and alter B cell proliferation and fate, 31 although increased fatty acid metabolism in germinal center localized B cells has also been reported. 46 hibition of the TCA cycle is that this allows excess citrate to feed into other anabolic pathways and succinate to promote inflammation. 49,50 Also, production of the bioactive metabolite itaconate is stimulated by pro-inflammatory stimuli.…”

Detection of Human CD38 Using Variable Lymphocyte Receptor (VLR) Tetramers

“…However, the use of tetVLRB MM3 tetramers in an antibody cocktail used for the analysis of tonsillar B cells revealed that GC centroblasts but not centrocytes preferentially reacted with tetVLRB MM3, indicating the increased occurrence of dimeric CD38 in these GC B cells. Studies on affinity maturation and class switch recombination occurring within the germinal center and differences between the centrocyte and centroblast B cell populations delineated the contributions of antigen receptors, costimulatory receptors, chemokine receptors, and regulatory effects on metabolic pathways in B and T cells [33][34][35]. Increased binding of tetVLRB MM3 to germinal center centroblasts indicated differential CD38 involvement on B lineage cells in the germinal center reaction, a facet of affinity maturation and class switch recombination that remains to be explored.…”