title: Preferential use of DH reading frame 2 alters B cell development and antigen-specific antibody production.
abstract: All jawed vertebrates limit use of D(H) reading frames (RFs) that are enriched for hydrophobic amino acids. In BALB/c mice, DFL16.1 RF2 encodes valine and isoleucine. To test whether increased use of RF2 affects B cell function, we examined B cell development and Ab production in mice with an IgH allele (DeltaD-DmicroFS) limited to use of a single, frameshifted DFL61.1 gene segment. We compared the results of these studies to wild-type mice, as well as those previously obtained in mice limited to use of either a single normal D(H) or a single inverted D(H) that forces use of arginine in CDR-H3. All three of the mouse strains limited to a single D(H) produced fewer immature B cells than wild type. However, whereas mice limited to a single normal D(H) achieved normal B cell numbers in the periphery, mice forced to preferentially use RF2 had reduced numbers of mature B cells in the spleen and bone marrow, mirroring the pattern previously observed in mice enriched for charged CDR-H3s. There were two exceptions. B cells in the mice using RF2 normally populated the marginal zone and peritoneal cavity, whereas mice using inverted RF1 had increased numbers of marginal zone B cells and decreased numbers of B1a cells. When challenged with several T-dependent or T-independent Ags, Ag-specific Ab titers in the mice forced to use RF2 were altered. These findings indicate that B cell development and Ag-specific Ab production can be heavily influenced by the global amino acid content of the CDR-H3 repertoire.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Schelonka
authors.forename: Michael
authors.initials: M
authors.lastname: Zemlin
authors.forename: Ryoki
authors.initials: R
authors.lastname: Kobayashi
authors.forename: Gregory C
authors.initials: GC
authors.lastname: Ippolito
authors.forename: Yingxin
authors.initials: Y
authors.lastname: Zhuang
authors.forename: G Larry
authors.initials: GL
authors.lastname: Gartland
authors.forename: Alex
authors.initials: A
authors.lastname: Szalai
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Fujihashi
authors.forename: Klaus
authors.initials: K
authors.lastname: Rajewsky
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder
mesh_terms: D000818:Animals; D000916:Antibody Diversity / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D022801:Complementarity Determining Regions / Q000235:genetics; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D016368:Frameshift Mutation; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D016364:Reading Frames / Q000235:genetics / Q000276:immunology*
chemical_list: D022801:Complementarity Determining Regions; D018985:Epitopes, B-Lymphocyte; D007143:Immunoglobulin Heavy Chains