title: TLR ligation triggers somatic hypermutation in transitional B cells inducing the generation of IgM memory B cells.
abstract: 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.
authors.affiliation: Research Center, Bambino Gesù Children's Hospital, 00165 Rome, Italy.
authors.forename: Alaitz
authors.initials: A
authors.lastname: Aranburu
authors.forename: Sara
authors.initials: S
authors.lastname: Ceccarelli
authors.forename: Ezio
authors.initials: E
authors.lastname: Giorda
authors.forename: Rosa
authors.initials: R
authors.lastname: Lasorella
authors.forename: Giovanna
authors.initials: G
authors.lastname: Ballatore
authors.forename: Rita
authors.initials: R
authors.lastname: Carsetti
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018858:Germinal Center / Q000166:cytology / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007135:Immunoglobulin Variable Region / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects* / Q000276:immunology; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D027041:Somatic Hypermutation, Immunoglobulin / Q000187:drug effects* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9