title: CpG drives human transitional B cells to terminal differentiation and production of natural antibodies.
abstract: The receptor TLR9, recognizing unmethylated bacterial DNA (CpG), is expressed by B cells and plays a role in the maintenance of serological memory. Little is known about the response of B cells stimulated with CpG alone, without additional cytokines. In this study, we show for the first time the phenotypic modification, changes in gene expression, and functional events downstream to TLR9 stimulation in human B cell subsets. In addition, we demonstrate that upon CpG stimulation, IgM memory B cells differentiate into plasma cells producing IgM Abs directed against the capsular polysaccharides of Streptococcus pneumoniae. This novel finding proves that IgM memory is the B cell compartment responsible for the defense against encapsulated bacteria. We also show that cord blood transitional B cells, corresponding to new bone marrow emigrants, respond to CpG. Upon TLR9 engagement, they de novo express AID and Blimp-1, genes necessary for hypersomatic mutation, class-switch recombination, and plasma cell differentiation and produce Abs with anti-pneumococcal specificity. Transitional B cells, isolated from cord blood, have not been exposed to pneumococcus in vivo. In addition, it is known that Ag binding through the BCR causes apoptotic cell death at this stage of development. Therefore, the ability of transitional B cells to sense bacterial DNA through TLR9 represents a tool to rapidly build up the repertoire of natural Abs necessary for our first-line defense at birth.
authors.affiliation: Laboratory of B-cell Development Research Center, Department of Medical and Surgical Neonatology, Children Hospital Bambino Gesù, and Department of Clinical Medicine, University of Rome La Sapienza, Italy. federica.capolunghi@opbg.net
authors.forename: Federica
authors.initials: F
authors.lastname: Capolunghi
authors.forename: Simona
authors.initials: S
authors.lastname: Cascioli
authors.forename: Ezio
authors.initials: E
authors.lastname: Giorda
authors.forename: Maria Manuela
authors.initials: MM
authors.lastname: Rosado
authors.forename: Alessandro
authors.initials: A
authors.lastname: Plebani
authors.forename: Cinzia
authors.initials: C
authors.lastname: Auriti
authors.forename: Giulio
authors.initials: G
authors.lastname: Seganti
authors.forename: Roberta
authors.initials: R
authors.lastname: Zuntini
authors.forename: Simona
authors.initials: S
authors.lastname: Ferrari
authors.forename: Maria
authors.initials: M
authors.lastname: Cagliuso
authors.forename: Isabella
authors.initials: I
authors.lastname: Quinti
authors.forename: Rita
authors.initials: R
authors.lastname: Carsetti
mesh_terms: D000917:Antibody Formation / Q000187:drug effects; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology*; D003564:Cytidine Deaminase / Q000378:metabolism; D004269:DNA, Bacterial / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007075:Immunoglobulin M / Q000096:biosynthesis; D007156:Immunologic Memory; D008213:Lymphocyte Activation; D010770:Phosphotransferases / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology; D011134:Polysaccharides / Q000276:immunology; D013154:Spleen / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D007075:Immunoglobulin M; D011134:Polysaccharides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D010770:Phosphotransferases; C117827:PnpS protein, Streptococcus pneumoniae; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase