title: Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin.
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.
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Rother
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Norway.|Volvat Medical Center, Oslo, Norway.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jensen
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Fleur S
authors.initials: FS
authors.lastname: van de Bovenkamp
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Roel
authors.initials: R
authors.lastname: Kroek
authors.affiliation: Center for Biomics, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Wilfred F J
authors.initials: WF
authors.lastname: van IJcken
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Vincent H J
authors.initials: VH
authors.lastname: van der Velden
authors.affiliation: Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Cupedo
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Norway.|Volvat Medical Center, Oslo, Norway.
authors.forename: Ole K
authors.initials: OK
authors.lastname: Olstad
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.affiliation: Department of Immunology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.|Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm