Multiple factors influence the contribution of individual immunoglobulin light chain genes to the naïve antibody repertoire

BMC Immunology

Marjorie A Shapiro¹  Kathleen J Clark¹  Antonina G Aydanian¹  Sean P Fitzsimmons¹ 

[1] Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, OBP, CDER, FDA, 10903 New Hampshire Avenue, Silver Spring 20993, MD, USA

关键词: Tonic signaling;    Rodent;    Receptor editing;    Generation of diversity;    Antibodies;    B lymphocytes;   

Others  :  1077682
DOI  :  10.1186/s12865-014-0051-2

 received in 2013-12-05, accepted in 2014-10-17,  发布年份 2014

【 摘 要 】

Background

The naïve antibody repertoire is initially dependent upon the number of germline V(D)J genes and the ability of recombined heavy and light chains to pair. Individual VH and VL genes are not equally represented in naïve mature B cells, suggesting that positive and negative selection also shape the antibody repertoire. Among the three member murine Vκ10 L chain family, the Vκ10C gene is under-represented in the antibody repertoire. Although it is structurally functional and accessible to both transcriptional and recombination machinery, the Vκ10C promoter is inefficient in pre-B cell lines and productive Vκ10C rearrangements are lost as development progresses from pre-B cells through mature B cells. This study examined VH/Vκ10 pairing, promoter mutations, Vκ10 transcript levels and receptor editing as possible factors that are responsible for loss of productive Vκ10C rearrangements in developing B cells.

Results

We demonstrate that the loss of Vκ10C expression is not due to an inability to pair with H chains, but is likely due to a combination of other factors. Levels of mRNA are low in sorted pre-B cells and undetectable in B cells. Mutation of a single base in the three prime region of the Vκ10C promoter increases Vκ10C promoter function in pre-B cell lines. Pre-B and B cells harbor disproportionate levels of receptor-edited productive Vκ10C rearrangements.

Conclusions

Our findings suggest that the weak Vκ10C promoter initially limits the amount of available Vκ10C L chain for pairing with H chains, resulting in sub-threshold levels of cell surface B cell receptors, insufficient tonic signaling and subsequent receptor editing to limit the numbers of Vκ10C-expressing B cells emigrating from the bone marrow to the periphery.

【 授权许可】

   
2014 Fitzsimmons et al.; licensee BioMed Central Ltd.

【 图 表 】

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