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Highlights d CD27 dull and CD27 bright MBCs share their VH repertoire but have different functions d CD27 dull MBCs are the long-lived substrate of selected and specific CD27 bright MBCs d The interplay between CD27 dull and CD27 bright MBCs preserves B cell memory d In pregnancy, MBCs decline, but persisting CD27 dull MBCs re-expand after delivery

TLR9 activation by unmethylated CpG provides a homeostatic mechanism to maintain B cell memory in the absence of Ag. In this study, we demonstrate that CpG also triggers the generation of somatically mutated memory B cells from immature transitional B cells. In response to CpG, a fraction of transitional B cells proliferates and introduces somatic hypermutations in the H chain V regions. The nonproliferating pool of transitional B cells mostly maintains germline configurations. Mutations are VH specific: VH5 is the least mutated family, whereas VH1 and VH4/6 are the most mutated families. CpG stimulation also results in upregulation of VH5 transcripts in proliferating cells. Therefore, early recognition of bacterial DNA preferentially expands VH5-expressing B cells while inducing somatic hypermutations in other families. The mutation frequency, range, and type of substitutions observed in vitro are comparable to those found in memory B cells from the peripheral blood of Hyper IgM type 1 patients and the spleen of normal infants. The process triggered by TLRs may represent a first step leading to additional diversification of the germline repertoire and to the generation of memory B cells that will further refine their repertoire and specificity in the germinal centers.

Switched and IgM memory B cells execute different and noninterchangeable functions.We studied memory B cells in children of different ages, in peripheral blood and spleen and compared them with those of children born asplenic or unable to build germinal centers. We show that, whereas switched memory B cells are mostly generated in the germinal centers at all ages, IgM memory B cells can be distinct in three types with different developmental history. Innate IgM memory B cells, the largest pool in infants, are generated in the spleen by a germinal center-independent mechanism. With age, if the spleen is present and germinal centers are functional, innate IgM memory B cells are remodelled and accumulate somatic mutations. The third type of IgM memory B cell is a by-product of the germinal center reaction. Our data suggest that the B-cell memory developmental program is implemented during the first 5-6 years of life. Keywords:Antibodies r B cells r B cell development r Immunoglobulins r Innate immunity Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Rita Carsetti e-mail: rita.carsetti@opbg.net * These authors contributed equally to this work.The copyright line for this article was changed on 9th February 2018 after original online publication.C 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 328Alaitz Aranburu et al. Eur. J. Immunol. 2017. 47: 327-344 IntroductionImmunological memory is the ability of the immune system to recognize and neutralize a previously encountered pathogen, thereby preventing re-infection and disease. Memory is acquired by the immune system through experience. Infants lack immunological memory and have a high risk of infections. The rate of infection and mortality is highest in infants and declines after the age of 5. The decline of child mortality in the last century has been one of the most significant achievements in medical history and is largely due to the introduction of vaccination and use of antibiotics. The first response to infection or vaccination generates the elements of memory: long-lived plasma cells and memory B cells [1][2][3][4]. Long-lived plasma cells continuously secrete specific antibodies (Abs) that upon re-infection will exert the first protection. Memory B cells rapidly react to the renewed challenge and produce Abs when and where these are most needed, i.e. when the pathogen again tries to invade the organism and at the site of its entry.In the adult, 50% of the B cells in the peripheral blood (PB) are memory B cells [5]. Phenotypically memory B cells can be identified by the expression of the CD27 marker. B cells that express CD27 carry somatic mutations in their immunoglobulin (Ig) genes [6]. These are permanent genetic imprints left by the mechanism of Somatic Hyper Mutation (SHM). Somatic mutations are triggered by activation events and results from the combined action of the activation-induced deaminase AID, the uracil-DNA glycosylase UNG and several DNA...