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.

Terminal Deoxynucleotidyl Transferase Is Not Required for Antibody Response to Polysaccharide Vaccines against Streptococcus pneumoniae and Salmonella enterica Serovar Typhi

“…TdT expression early in life temporally coincides with IL-7-dependent B lymphopoiesis. For example, human fetal B cell precursors have reduced expression of both IL-7 receptor ␣ (IL-7R␣) and TdT (19). Furthermore, humans with IL-7R␣ mutations have reduced expression of TdT in their pro-B cells (19).…”

“…For example, human fetal B cell precursors have reduced expression of both IL-7 receptor ␣ (IL-7R␣) and TdT (19). Furthermore, humans with IL-7R␣ mutations have reduced expression of TdT in their pro-B cells (19). We have previously shown that murine antibody responses to Pneumovax23 require IL-7 (3).…”

“…Mice deficient in IL-7R␣ signaling have a restricted immunoglobulin repertoire, partly because they are inefficient in their usage of distal V H gene segments during V(D)J recombination (42), similar to the inefficiency of the usage of distal V H gene segments seen in newborn mice (43). Human pro-B cells that develop early in life express mainly proximal V H rather than distal V H segments (19). It was previously shown that the majority of adult human B cells that bind to PPS serotypes 14 and 4 utilize distal V H genes V H 3-74 and V H 3-48 (44), whereas those that bind to PPS serotypes 6b and 23f utilize the V H 3-23 located in the center of the human Ig heavy-chain locus (45,46).…”

“…Notably, fetal B immunoglobulin gene rearrangements use third-heavy-chain complementarity-determining regions (HCDR3s) shorter than those from adults (17,18). The developing B cells of human infants also express significantly reduced levels of TdT compared to B cells of older children (19). Consistent with this, the B cells of infants but not older children express antibody V genes with reduced numbers of N nucleotides at the junctions of the V-D, D-J, and V-J gene segments (19).…”

“…The developing B cells of human infants also express significantly reduced levels of TdT compared to B cells of older children (19). Consistent with this, the B cells of infants but not older children express antibody V genes with reduced numbers of N nucleotides at the junctions of the V-D, D-J, and V-J gene segments (19). Therefore, it was previously hypothesized that infants and young children respond poorly to PS antigens due to reduced BCR junctional diversity (10,11).…”