title: Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory.
abstract: Somatic hypermutation (SHM) and class-switch recombination (CSR) increase the affinity and diversify the effector functions of antibodies during immune responses. Although SHM and CSR are fundamentally different, their independent roles in regulating B cell fate have been difficult to uncouple because a single enzyme, activation-induced cytidine deaminase (encoded by Aicda), initiates both reactions. Here, we used a combination of Aicda and antibody mutant alleles that separate the effects of CSR and SHM on polyclonal immune responses. We found that class-switching to IgG1 biased the fate choice made by B cells, favoring the plasma cell over memory cell fate without significantly affecting clonal expansion in the germinal center (GC). In contrast, SHM reduced the longevity of memory B cells by creating polyreactive specificities that were selected against over time. Our data define the independent contributions of SHM and CSR to the generation and persistence of memory in the antibody system.
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA. Electronic address: agitlin@rockefeller.edu.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Gitlin
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA.
authors.forename: Lotta
authors.initials: L
authors.lastname: von Boehmer
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Gazumyan
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA.
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA.
authors.forename: Thiago Y
authors.initials: TY
authors.lastname: Oliveira
authors.affiliation: Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065 USA; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065 USA. Electronic address: nussen@rockefeller.edu.
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics*; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007074:Immunoglobulin G; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase