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

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

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10 Citations (Scopus)

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.

Original languageEnglish
Article number33924
Number of pages13
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 23 Sep 2016

Keywords

  • molecular medicine
  • VDJ recombination

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