Timely and spatially regulated maturation of B and T cell repertoire during human fetal development

Erez Rechavi, Atar Lev, Yu Nee Lee, Amos J. Simon, Yoav Yinon, Schlomo Lipitz, Ninette Amariglio, Boaz Weisz, Luigi D. Notarangelo, Raz Somech

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

Abstract

Insights into the ontogeny of the human fetal adaptive immune system are of great value for understanding immunocompetence of the developing fetus. However, to date, this has remained largely uncharted territory, in large part because blood samples from healthy, early gestation fetuses have been hard to come by. In a comprehensive study, we analyzed levels of T cell receptor excision circles (TRECs), signal-joint κ receptor excision circles (sjKRECs), and intron recombination signal sequence-K-deleting element (iRSS-Kde) rearrangement, and T and B lymphocyte repertoire clonality in human fetuses from 12 to 26 weeks of gestational age. Using next-generation sequencing, we analyzed the diversity and complexity of T cell receptor β (TRB) and immunoglobulin heavy chain (IGH) repertoires in four fetuses at 12, 13, 22, and 26 weeks of gestation and in healthy full-term infants. We report the progressive increase of TREC, sjKREC, and iRSS-Kde levels over time and confirm that B cell development precedes T cell development in the human fetus. Temporally and spatially regulated maturation of B and T cell repertoire diversity and complexity during human fetal development was observed, including evidence that immunoglobulin somatic hypermutation and class switch recombination occur already during intrauterine life. Our results help define physiological levels of immunodeficiency in premature infants and may serve as a reference for future studies aimed at investigating the impact of intrauterine pathologies on fetal immune development and function.

Original languageEnglish
Article number276ra25
JournalScience Translational Medicine
Volume7
Issue number276
DOIs
StatePublished - 25 Feb 2015
Externally publishedYes

Bibliographical note

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© 2015, American Association for the Advancement of Science. All rights reserved.

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