Fasting impairs humoral immunological memory by β-hydroxybutyrate-mediated depletion of plasma cells

Humoral immunological memory mediated by memory B cells (MBCs) and long-lived plasma cells (LLPCs) is critical for sustained protection following infection or vaccination. LLPCs protect the hosts by secreting protective neutralizing antibodies over extended periods. However, the mechanism regulating their survival and thus the durability of protective antibodies remains unclear. Here, we showed in human and mouse models that intermittent fasting impaired humoral immunological memory by accelerating antibody decay. Fasting selectively depleted LLPCs while sparing MBCs in mice. Mechanistically, this effect was mediated by increased extracellular β-hydroxybutyrate, a ketone body produced during fasting, which acted through the hydroxycarboxylic acid receptor 2 (HCAR2) on plasma cells. Activation of the HCAR2-Gαi-adenylate cyclase-cAMP axis by β-hydroxybutyrate downregulated CXCR4, leading plasma cells to exit their bone marrow niche and undergo apoptosis in the periphery. These findings reveal that fasting-induced metabolic signals regulate humoral immunity duration and suggest that diet and lifestyle could influence vaccine effectiveness.