RRC ID 18535
Author Kaji T, Ishige A, Hikida M, Taka J, Hijikata A, Kubo M, Nagashima T, Takahashi Y, Kurosaki T, Okada M, Ohara O, Rajewsky K, Takemori T.
Title Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory.
Journal J Exp Med
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.
Volume 209(11)
Pages 2079-97
Published 2012-10-22
DOI 10.1084/jem.20120127
PII jem.20120127
PMID 23027924
PMC PMC3478929
MeSH Animals Antibodies / genetics Antibodies / immunology* Antibodies / metabolism B-Lymphocytes / immunology* B-Lymphocytes / metabolism DNA-Binding Proteins / genetics DNA-Binding Proteins / immunology DNA-Binding Proteins / metabolism Female Flow Cytometry Gene Expression Profiling Germ Cells / immunology* Germ Cells / metabolism Germinal Center / immunology* Germinal Center / metabolism Immunoglobulin G / genetics Immunoglobulin G / immunology Immunoglobulin G / metabolism Immunoglobulin Heavy Chains / genetics Immunoglobulin Heavy Chains / immunology Immunoglobulin Heavy Chains / metabolism Immunoglobulin Variable Region / genetics Immunoglobulin Variable Region / immunology Immunoglobulin Variable Region / metabolism Immunologic Memory / immunology* Male Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Molecular Sequence Data Oligonucleotide Array Sequence Analysis Proto-Oncogene Proteins c-bcl-6 Reverse Transcriptase Polymerase Chain Reaction Sequence Analysis, DNA Signal Transduction / genetics Signal Transduction / immunology*
IF 10.892
Times Cited 145
WOS Category MEDICINE, RESEARCH & EXPERIMENTAL IMMUNOLOGY
Resource
Mice B6-Tg(CAG-FLPe)36 (RBRC01834) B6-Tg(CAG-FLPe)37 (RBRC01835)