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Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):E2622-9. doi: 10.1073/pnas.1403278111. Epub 2014 Jun 9.

Antibody repertoire deep sequencing reveals antigen-independent selection in maturing B cells.

Author information

1
Department of Pathology andDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115; and.
2
Department of Pathology, New York University Medical Center, New York, NY 10016.
3
Department of Pathology andDepartment of Systems Biology, Harvard Medical School, Boston, MA 02115; andDivision of Clinical Informatics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; rarnaout@gmail.com.

Abstract

Antibody repertoires are known to be shaped by selection for antigen binding. Unexpectedly, we now show that selection also acts on a non-antigen-binding antibody region: the heavy-chain variable (VH)-encoded "elbow" between variable and constant domains. By sequencing 2.8 million recombined heavy-chain genes from immature and mature B-cell subsets in mice, we demonstrate a striking gradient in VH gene use as pre-B cells mature into follicular and then into marginal zone B cells. Cells whose antibodies use VH genes that encode a more flexible elbow are more likely to mature. This effect is distinct from, and exceeds in magnitude, previously described maturation-associated changes in heavy-chain complementarity determining region 3, a key antigen-binding region, which arise from junctional diversity rather than differential VH gene use. Thus, deep sequencing reveals a previously unidentified mode of B-cell selection.

KEYWORDS:

development; immunomics; principal component analysis

PMID:
24927543
PMCID:
PMC4078805
DOI:
10.1073/pnas.1403278111
[Indexed for MEDLINE]
Free PMC Article

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