Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27dull and CD27bright MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27dull and CD27bright MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27dull into the CD27bright MBC pool. 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. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27dull clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27dull MBCs that expand and differentiate in response to change.

B Cell Pathophysiology Unit Immunology Research Area Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy

B Cell Pathophysiology Unit Immunology Research Area Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy; Department of Rheumatology and Inflammation Research University of Gothenburg Box 480 405 30 Gothenburg Sweden

B Cell Pathophysiology Unit Immunology Research Area Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy; Diagnostic Immunology Unit Department of Laboratories Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy

Central European Institute of Technology 625 00 Brno Czech Republic

Central European Institute of Technology 625 00 Brno Czech Republic; Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry 117997 Moscow Russia; Institute of Translational Medicine Pirogov Russian National Research Medical University 117997 Moscow Russia; Center of Life Sciences Skolkovo Institute of Science and Technology 101000 Moscow Russia

Department of Experimental and Clinical Sciences University of Brescia 25121 Brescia Italy

Department of Obstetrics and Gynaecology Misericordia Hospital Grosseto Usl Toscana Sud est 58100 Grosseto Italy

Department of Rheumatology and Inflammation Research University of Gothenburg Box 480 405 30 Gothenburg Sweden

Division of Rheumatology Bambino Gesù Children's Hospital IRCCS 00146 Roma Italy

DPUO Division of Immuno Infectivology University Department of Pediatrics 00146 Bambino Gesù Children's Hospital Rome Italy

DPUO Division of Immuno Infectivology University Department of Pediatrics 00146 Bambino Gesù Children's Hospital Rome Italy; School of Medicine University of Tor Vergata 00133 Rome Italy

Genetics and Rare Diseases Research Division Bambino Gesù Children's Hospital 00146 Rome Italy

Istituto Dermopatico dell'Immacolata IRCCS 00167 Rome Italy

Multifactorial Disease and Complex Phenotype Research Area Bambino Gesù Children's Hospital IRCSS 00146 Rome Italy

Occupational Medicine Health Technology Assessment and Safety Research Unit Clinical Technological Innovations Research Area Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy

Oncohaematology Department Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy

Oncohaematology Department Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy; Department of Pediatrics Sapienza University of Rome 00161 Rome Italy

Otorhinolaryngology Unit Bambino Gesù Children's Hospital IRCSS 00146 Rome Italy

Pediatric and Infectious Disease Unit Bambino Gesù Children's Hospital IRCCS 00146 Rome Italy

Pediatric Immunology Unit Policlinico Tor Vergata University of Rome Tor Vergata 00133 Rome Italy

Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry 117997 Moscow Russia; Center of Life Sciences Skolkovo Institute of Science and Technology 101000 Moscow Russia

Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry 117997 Moscow Russia; Institute of Translational Medicine Pirogov Russian National Research Medical University 117997 Moscow Russia; Center of Life Sciences Skolkovo Institute of Science and Technology 101000 Moscow Russia

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