TY - JOUR
T1 - Decreased IL7Rα and TdT expression underlie the skewed immunoglobulin repertoire of human B-cell precursors from fetal origin
AU - Rother, Magdalena B.
AU - Jensen, Kristin
AU - van der Burg, Mirjam
AU - van de Bovenkamp, Fleur S.
AU - Kroek, Roel
AU - van Ijcken, Wilfred F. J.
AU - van der Velden, Vincent H. J.
AU - Cupedo, Tom
AU - Olstad, Ole K.
AU - van Dongen, Jacques J. M.
AU - Van Zelm, Menno C.
PY - 2016/9/23
Y1 - 2016/9/23
N2 - 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.
AB - 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.
KW - molecular medicine
KW - VDJ recombination
UR - http://www.scopus.com/inward/record.url?scp=84988568814&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/27658954
U2 - 10.1038/srep33924
DO - 10.1038/srep33924
M3 - Article
C2 - 27658954
AN - SCOPUS:84988568814
VL - 6
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 33924
ER -