IL-7R signaling activates widespread V(H) and D(H) gene usage to drive antibody diversity in bone marrow B cells

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.