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

Immunocompetence in the developing fetus is temporally and spatially regulated. Developing Immunity The adaptive immune response plays a critical role in protecting the body from both foreign pathogens and internal dangers such as cancer. However, little is known about how the immune system develops during human gestation. Rechavi et al. analyzed differences in B and T lymphocyte ontogeny from 12 to 26 weeks of gestational age. They found that B cell development precedes T cell development and that repertoire maturation is both temporally and spatially regulated. These data can be used as a baseline to improve immune function in developing fetuses and to assess the effects of therapeutic interventions. 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.

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