IL-7R signaling activates widespread VH and DH gene usage to drive antibody diversity in bone marrow B cells

Summary Generation of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain ( Igh ) locus. The role of interleukin-7 receptor (IL-7R) signaling in Igh recombination has been difficult to partition from its role in B cell survival and proliferation. With a detailed description of the Igh repertoire in murine IL-7Rα −/− bone marrow B cells, we demonstrate that IL-7R signaling profoundly influences V H gene selection during V H -to-DJ H recombination. We find skewing toward 3′ V H genes during de novo V H -to-DJ H recombination more severe than the fetal liver (FL) repertoire and uncover a role for IL-7R signaling in D H -to-J H recombination. Transcriptome and accessibility analyses suggest reduced expression of B lineage transcription factors (TFs) and targets and loss of D H and V H antisense transcription in IL-7Rα −/− B cells. Thus, in addition to its roles in survival and proliferation, IL-7R signaling shapes the Igh repertoire by activating underpinning mechanisms.