title: Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory.
abstract: One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell-dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell-dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen.
authors.affiliation: Laboratory for Immunological Memory, RIKEN Research Center for Allergy and Immunology, Tsurumi, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaji
authors.forename: Akiko
authors.initials: A
authors.lastname: Ishige
authors.forename: Masaki
authors.initials: M
authors.lastname: Hikida
authors.forename: Junko
authors.initials: J
authors.lastname: Taka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hijikata
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Yoshimasa
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kurosaki
authors.forename: Mariko
authors.initials: M
authors.lastname: Okada
authors.forename: Osamu
authors.initials: O
authors.lastname: Ohara
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Toshitada
authors.initials: T
authors.lastname: Takemori
mesh_terms: D000818:Animals; D000906:Antibodies / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005854:Germ Cells / Q000276:immunology* / Q000378:metabolism; D018858:Germinal Center / Q000276:immunology* / Q000378:metabolism; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D051560:Proto-Oncogene Proteins c-bcl-6; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
chemical_list: D000906:Antibodies; C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D051560:Proto-Oncogene Proteins c-bcl-6