HIF1? Affects Humoral Immunity By Regulating B Cell Metabolic Reprogramming In Germinal Center Reaction

Warburg effect(aerobic glycolysis)is first described as a metabolic profile of tumors in normoxic conditions and soon become one of the hallmarks of cancer cells,in which glycolysis predominates even though there is oxygen available for oxidative metabolism to proceed.Studies of immune system metabolism have showed this special metabolic reprogramming playing an important role in many kinds of immunocytes,including neutrophils,macrophages,dendritic cells and T cells.We have learned that B cells do share certain fundamental metabolic characteristics with T cells,such as a metabolic shift upon activation,however,most of these studies were just in vitro experiments and much less is known about the B cell metabolism in vivo.Hypoxia-inducible factor-1 alpha(HIF1?)has been implicated in regulating many of the genes that are responsible for aerobic glycolysis,but its function is always considered with hypoxia not metabolism in B cell.Here,through analysing the genes expression and oxygen consumption rates of B cell subpopulation from human and mice,we described a model of B cells metabolic reprogramming during germinal center reaction,which was regulated by HIF1?.At the stage of centroblasts,aerobic glycolysis provided energy for B cell proliferation.When converted to centrocytes,oxidative phosphorylation was the dominated pathway for providing energy.This led to anaerobic environment of light zone due to the limit of oxygen concentration in immune organs.And anaerobic glycolysis may supplement energy for centrocytes.While the highly expression of mammalian target of rapamycin(m TOR)may induce HIF1? expressing in the germinal center B cells,the deficiency of HIF1? in B cells can impair the germinal center reaction by affinity maturation,class switch recombination(CSR)and high-affinity plasma cell generation.Thus we identified the role of HIF1? in humoral immunity from a metabolic point of view.