Metabolic Reprogramming Induces Germinal Center B Cell Differentiation Through Epigenetic Control of <i>Bcl6</i> Expression

Abstract

The germinal center (GC) reaction is essential for long-lived humoral immunity. However, molecular requirements for the induction of Bcl6, the master regulator for GC B cell differentiation, remain unclear. Through screening for cytokines and other stimuli that regulate Bcl6 expression, we identified IL-4 as the strongest inducer. IL-4-signaling altered the metabolomic profile in activated B cells and induced accumulation of the TCA cycle intermediate α-ketoglutarate (αKG), which was required for epigenetic activation of the Bcl6 gene locus. Mechanistically, after IL-4-treatment, STAT6 bound to the known enhancers in the Bcl6 locus and recruited UTX, a demethylase for the repressive histone mark H3K27me3 that requires αKG as a cofactor. In turn, the H3K27me3 demethylation activated the enhancers and transcription of the Bcl6 gene. We propose that IL-4-medicated metabolic reprogramming in B cells is the key factor that regulates epigenetic activation of the master regulator of GC B cell differentiation.