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Sci Immunol. 2016 Jul 14;1(1). pii: aaf6628. doi: 10.1126/sciimmunol.aaf6628.

VpreB serves as an invariant surrogate antigen for selecting immunoglobulin antigen-binding sites.

Author information

1
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Division of Genetic Engineering, National Research Center of Egypt, Cairo, Egypt.
2
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
3
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.
4
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.

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 DH gene-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.

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