title: Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways.
abstract: Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27⁻IgG⁺ and CD27⁺IgM⁺ B cells are derived from primary germinal center reactions, and CD27⁺IgA⁺ and CD27⁺IgG⁺ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27⁻IgA⁺ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27⁻IgA⁺ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.
authors.affiliation: Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Magdalena A
authors.initials: MA
authors.lastname: Berkowska
authors.forename: Gertjan J A
authors.initials: GJ
authors.lastname: Driessen
authors.forename: Vasilis
authors.initials: V
authors.lastname: Bikos
authors.forename: Christina
authors.initials: C
authors.lastname: Grosserichter-Wagener
authors.forename: Kostas
authors.initials: K
authors.lastname: Stamatopoulos
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.forename: Katharina
authors.initials: K
authors.lastname: Biermann
authors.forename: Johan F
authors.initials: JF
authors.lastname: Lange
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
mesh_terms: D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*; D001483:Base Sequence; D023201:CD40 Ligand / Q000172:deficiency; D002454:Cell Differentiation / Q000276:immunology; D004247:DNA / Q000235:genetics; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000145:classification / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000145:classification / Q000235:genetics / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D007156:Immunologic Memory; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D018448:Models, Immunological; D008969:Molecular Sequence Data; D010641:Phenotype; D027041:Somatic Hypermutation, Immunoglobulin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D023201:CD40 Ligand; D004247:DNA