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Proc Natl Acad Sci U S A. 2011 Mar 29;108(13):5348-53. doi: 10.1073/pnas.1014277108. Epub 2011 Mar 10.

Determinism and stochasticity during maturation of the zebrafish antibody repertoire.

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  • 1Department of Bioengineering, Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.

Abstract

It is thought that the adaptive immune system of immature organisms follows a more deterministic program of antibody creation than is found in adults. We used high-throughput sequencing to characterize the diversifying antibody repertoire in zebrafish over five developmental time points. We found that the immune system begins in a highly stereotyped state with preferential use of a small number of V (variable) D (diverse) J (joining) gene segment combinations, but that this stereotypy decreases dramatically as the zebrafish mature, with many of the top VDJ combinations observed in 2-wk-old zebrafish virtually disappearing by 1 mo. However, we discovered that, in the primary repertoire, there are strong correlations in VDJ use that increase with zebrafish maturity, suggesting that VDJ recombination involves a level of deterministic programming that is unexpected. This stereotypy is masked by the complex diversification processes of antibody maturation; the variation and lack of correlation in full repertoires between individuals appears to be derived from randomness in clonal expansion during the affinity maturation process. These data provide a window into the mechanisms of VDJ recombination and diversity creation and allow us to better understand how the adaptive immune system achieves diversity.

PMID:
21393572
[PubMed - indexed for MEDLINE]
PMCID:
PMC3069157
Free PMC Article
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