title: VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites.
abstract: Developmental checkpoints eliminate B cells synthesizing defective immunoglobulin heavy (HC) and light (LC) chains. The first checkpoint tests for formation of a VpreB/λ5/µHC-containing preB-cell receptor (preBCR) and predicts whether µHCs will bind conventional LCs to form membrane IgM. VpreB and λ5 also create a sensing site that interacts with µHC antigen-binding region CDR-H3, but whether it plays a role in immunoglobulin repertoire selection and function is unknown. On a position-by-position basis, we analyzed the amino acid content of CDR-H3s from H chains cloned from living and apoptotic preB cells and from IgG:Antigen structures. Using a panel of DHgene-targeted mice, we show that progressively reducing CDR-H3 tyrosine content increasingly impairs preBCR checkpoint passage. Counting from cysteine at Framework 3 position 96, we found that VpreB particularly selects for tyrosine at CDR-H3 position 101, and that Y101 also binds antigen in IgG:Antigen structures. VpreB thus acts as an early invariant antigen. It selects for particular CDR-H3 amino acids and shapes the specificity of the IgG humoral response. This helps explain why some neutralizing antibodies against pathogens are readily produced while others are rare.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Division of Genetic Engineering, National Research Center of Egypt, Cairo, Egypt.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Khass
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Tessa
authors.initials: T
authors.lastname: Blackburn
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Burrows
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Walter
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL; Institute for Mathematical Modeling of Biological Systems, Department of Biology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Emidio
authors.initials: E
authors.lastname: Capriotti
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: Harry W
authors.initials: HW
authors.lastname: Schroeder