The interplay between CD27dull and CD27bright B cells ensures the flexibility, stability and resilience of human B-cell memory

Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment with the function of preventing infection. MBCs are first generated in infancy and exert protection throughout life. We identify two MBCs subsets in the peripheral blood: CD27dull MBCs and CD27bright MBCs, whose frequency changes with age. VH usage, somatic mutation frequency, replacement-to-silent ratio, and CDR3 properties changes all demonstrate that CD27dull and CD27bright MBCs represent sequential MBC developmental stages and stringent antigen-driven pressure selects CD27dull into the CD27bright MBC pool. Transcriptome and functional assays indicate that CD27dull MBCs are intermediate between naive and CD27bright MBCs, which, in turn, are closer to the effector plasma cell stage. Dynamics of human MBCs are exploited in pregnancy when 50% of maternal MBCs are lost and CD27dull MBCs transit to the more differentiated CD27bright stage. At this time, maternal antibodies increase and are transported to the fetus for its protection after birth. In the post-partum, the maternal MBC pool is rapidly replenished by the expansion of persistent CD27dull clones. Thus, the stability and flexibility of human B cell memory is ensured by the existence of CD27dull MBCs that have the capacity to expand and differentiate in response to change. The strategy of the human MBC response explains the evolution of the B-cell response to infectious diseases, provides a rationale for the design of age-tailored vaccines and explains the reduced protective function of B cells at the extreme ages.