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

Abstract

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.

Keywords: B lymphocyte development; Igh recombination; Pax5 transcription factor; antisense transcription; bone marrow; chromatin accessibility; fetal liver; interleukin-7 receptor signaling; pro-B cells.