Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin.

Magdalena B Rother,Wilfred F J Van Ijcken,Jacques J M Van Dongen,Tom Cupedo,Roel Kroek,Kristin Jensen,Ole K Olstad,Fleur S Van De Bovenkamp,Vincent H J Van Der Velden,Menno C Van Zelm,Mirjam Van Der Burg

doi:10.1038/srep33924

Magdalena B Rother, Wilfred F J Van Ijcken + Show 9 more

Open Access

https://doi.org/10.1038/srep33924

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Abstract

Newborns are unable to mount antibody responses towards certain antigens. This has been related to the restricted repertoire of immunoglobulin (Ig) genes of their B cells. The mechanisms underlying the restricted fetal Ig gene repertoire are currently unresolved. We here addressed this with detailed molecular and cellular analysis of human precursor-B cells from fetal liver, fetal bone marrow (BM), and pediatric BM. In the absence of selection processes, fetal B-cell progenitors more frequently used proximal V, D and J genes in complete IGH gene rearrangements, despite normal Ig locus contraction. Fewer N-nucleotides were added in IGH gene rearrangements in the context of low TdT and XRCC4 expression. Moreover, fetal progenitor-B cells expressed lower levels of IL7Rα than their pediatric counterparts. Analysis of progenitor-B cells from IL7Rα-deficient patients revealed that TdT expression and N-nucleotides additions in Dh-Jh junctions were dependent on functional IL7Rα. Thus, IL7Rα affects TdT expression, and decreased expression of this receptor underlies at least in part the skewed Ig repertoire formation in fetal B-cell precursors. These new insights provide a better understanding of the formation of adaptive immunity in the developing fetus.

Highlights

During the second trimester of human fetal development, B cells are generated in the liver and bone marrow (BM), providing the neonate with a diverse immunoglobulin (Ig) repertoire
In line with previous observations[1,16,17,20,21,24,25,27,34], mature B cells (CD19+CD20+CD10-IgM+IgD+)in fetal BM showed more frequent usage of Vh1-2, Dh7-27, Jh2 and Jh3 genes than pediatric B cells (Supplementary Fig. 1)[23]. This Ig heavy chain (IGH) gene usage was typical for early development, because the IGH repertoire in B cells from neonatal cord blood was more similar to pediatric than to fetal B cells (Supplementary Fig. 1)
Fetal B-cell progenitors are generated with a skewed IGH gene repertoire, which is similar between fetal liver and fetal BM, and does not seem to be affected by selection processes

Summary

Introduction

During the second trimester of human fetal development, B cells are generated in the liver and bone marrow (BM), providing the neonate with a diverse immunoglobulin (Ig) repertoire. Several studies have addressed the Ig gene repertoire in human fetuses, and reported restricted repertoires due to shorter CDR3 regions in IGH This restriction was the result of limited N-nucleotides in the junctions and more frequent usage of the relatively short Dh7-27, Jh2 and Jh3 genes[1,2,14,15,16,17,18,19,20,21,22,23]. The Ig gene repertoire in progenitor-B cells of IL7Rα-deficient patients has not been studied so far It remains unclear what underlies the skewed Ig repertoire in fetal B cells and if IL-7R signaling is involved. Through analysis of patients with genetic defects in IL7Rα, we were able to demonstrate a direct link between IL7Rα, TdT and N-nucleotide additions in IGH gene rearrangements

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