Zfp318 controls the recallability of memory B cells

Memory B cells (MBCs) are important for efficacious antibody-based vaccines and develop via germinal center (GC)-dependent and -independent routes. We find all MBCs are not equally recallable by antigen. Zfp318, a transcription regulator of spermatogenesis and IgD expression, is not expressed in GC B cells but upregulated in MBCs. GC-derived MBCs are far more recallable than GC-independent MBCs in a Zfp318-dependent manner. Zfp318 expression is inhibited by BCR but promoted by CD40 signaling, while its levels are positively correlated with B-cell receptor affinities. Enforced Zfp318 expression markedly increases the recallability of GC-independent MBCs. Zfp318-deficient MBCs show reduced expression of mitochondrion-related genes, exhibit lower mitochondrial membrane potentials, contain more structurally compromised mitochondria, and are susceptible to activation-induced cell death. The abundance of Zfp318-expressing MBCs positively correlates with the quality of vaccine-induced antibody immunity. Therefore, Zfp318 defines the recallability of the MBC compartment and represents a key regulator of humoral immune memory. ### Competing Interest Statement Y.W. and H.Q. are co-founders of Emergent Biomed Solutions, Ltd.