Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Magdalena A. Berkowska, Gertjan J A Driessen, Vasilis Bikos, Christina Grosserichter-Wagener, Kostas Stamatopoulos, Andrea Cerutti, Bing He, Katharina Biermann, Johan F. Lange, Mirjam Van Der Burg, Jacques J M Van Dongen, Menno C. Van Zelm

Research output: Contribution to journalArticleResearchpeer-review

213 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2150-2158
Number of pages9
Issue number8
Publication statusPublished - 25 Aug 2011
Externally publishedYes

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