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Surrogate selection
A broad yet specific antibody response is critical to fight off pathogens; however, it remains unclear why certain antibodies may be more easily induced than others. Now, Khass et al. report that a component of the surrogate light chain—VpreB—may also act as an invariant antigen that contributes to shaping the antibody repertoire. They demonstrated that progressively reducing the tyrosine content of the heavy chain antigen recognition site impaired the ability of B cells expressing the pre-BCR to pass the first checkpoint. VpreB selected for particular amino acids in the complementarity-determining region of the heavy chain, shaping the subsequent antibody response.
Abstract
Developmental checkpoints eliminate B cells that synthesize defective immunoglobulin (Ig) heavy (HC) and light (LC) chains. The first checkpoint tests μHCs paired with VpreB/λ5 in a pre-B cell receptor (pre-BCR) to determine whether the μHC will be able to bind conventional LCs to form membrane IgM. VpreB and λ5 also create a sensing site that interacts with the μHC antigen-binding region complementarity-determining region (CDR)–H3; however, whether this site contributes to Ig repertoire selection and function is unknown. We analyzed the amino acid content of CDR-H3s from HCs cloned from living and apoptotic pre-B cells and from IgG-antigen structures. Using a panel of DH gene–targeted mice, we showed that progressively reducing CDR-H3 tyrosine content increasingly impaired pre-BCR checkpoint passage. Counting from cysteine at framework 3 position 96, we found that VpreB particularly selected for tyrosine at CDR-H3 position 101 and that Y101 also bound antigen in IgG-antigen structures. Therefore, in addition to its stabilization role in the pre-BCR, VpreB also acts as an early invariant antigen by selecting for particular CDR-H3 amino acids. These interactions shape the specificity of the IgG humoral response and may thus impose limitations on development of certain neutralizing antibodies.
- Copyright © 2016, American Association for the Advancement of Science
