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

• Published in: Cell reports (Cambridge) 2021-07, Vol.36 (2), p.109349
• Main Authors: Baizan-Edge, Amanda, Stubbs, Bryony A, Stubbington, Michael J T, Bolland, Daniel J, Tabbada, Kristina, Andrews, Simon, Corcoran, Anne E
• Format: Article
• Language: English
• Subjects: Animals; Antibody Diversity - genetics; B-Lymphocytes - metabolism; Base Sequence; Bone Marrow - metabolism; Cell Lineage - genetics; Chromatin - metabolism; DNA, Intergenic - genetics; Fetus - metabolism; Genes, Immunoglobulin Heavy Chain; Immunoglobulin Variable Region - genetics; Liver - embryology; Liver - metabolism; Mice; Mice, Inbred C57BL; Nucleotide Motifs - genetics; PAX5 Transcription Factor - metabolism; Receptors, Interleukin-7 - metabolism; Signal Transduction; Trans-Activators - metabolism; Transcription, Genetic
• ISSN: 2211-1247
• DOI: 10.1016/j.celrep.2021.109349

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 gene selection during V -to-DJ recombination. We find skewing toward 3' V genes during de novo V -to-DJ recombination more severe than the fetal liver (FL) repertoire and uncover a role for IL-7R signaling in D -to-J recombination. Transcriptome and accessibility analyses suggest reduced expression of B lineage transcription factors (TFs) and targets and loss of D and V 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.