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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/?5/µHC-containing preB-cell receptor (preBCR) and predicts whether µHCs will bind conventional LCs to form membrane IgM. VpreB and ?5 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.

SUBMITTER: Khass M

PROVIDER: S-EPMC5315267 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Khass Mohamed M Blackburn Tessa T Burrows Peter D PD Walter Mark R MR Capriotti Emidio E Schroeder Harry W HW

Science immunology 20160701 1

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-positio ...[more]

PMID: 28217764

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Dataset Information

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

Publications

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

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