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

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.

Infants Infected with Respiratory Syncytial Virus Generate Potent Neutralizing Antibodies that Lack Somatic Hypermutation

“…Also, the majority of antibodies isolated from the youngest three infants lacked SHM, similar to what was observed previously in postF-reactive B cells (Williams et al, 2009). However, nearly 5% of antibodies isolated from these infants had VH genes containing at least five nucleotide substitutions, consistent with previous studies showing that SHM does occur in young infants, albeit at relatively low frequency (Rechavi et al, 2015; Ridings et al, 1998). The level of SHM in antibodies isolated from the two infants ≥ 6 mo.…”

The Human Thymus Is Enriched for Autoreactive B Cells

“…In addition to thymic B cells, we also report, to our knowledge for the first time, on the reactivity of fetal BM-derived B cells. Although the repertoire of fetal B cells has been documented extensively (35,(39)(40)(41)(42)(43), the suggestion that these genes would encode autoreactive Abs has not been addressed before (44)(45)(46). In the present study, we showed that fetal B cell-derived Abs bind stronger to dsDNA than do pediatric BM-derived B cells.…”

XLF deficiency results in reduced N-nucleotide addition during V(D)J recombination

“…45,46 Recently, Rechavi et al have shown that fetal-derived lymphocytes also have reduced numbers of numbers of N-nucleotides in IgH and TRB rearrangements. 47 In addition, they showed preferential use of the DH-proximal VH genes IgHV6-1 and IgHV1-2 and the JH-proximal IgHD7-27 genes in the fetal IgH rearrangements. In contrast, the use of IgHV6-1, IgHV1-2, and IgHD7-27 was normal in the XLF-deficient patients (data not shown), suggesting it is not likely that the XLFdeficient patients have an increased frequency of the fetal-derived lymphocytes.…”