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bioRxiv · 10.1101/2020.09.24.298000

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

Baizan Edge, A.·Stubbs, B. A.·Stubbington, M. J. T.·Bolland, D. J.·Tabbada, K.·Andrews, S.·Corcoran, A. E.
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Abstract

Generation of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain (Igh) locus. It has been proposed that interleukin-7 receptor (IL-7R) signalling is necessary for Igh recombination, but this has been challenging to partition from the receptors role in B cell survival and proliferation. By generating the first detailed description of the Igh repertoire of murine IL-7R-/- bone marrow B cells, we demonstrate that IL-7R signalling profoundly influences VH gene selection during VH-to-DJH recombination. We find skewing towards usage of 3 VH genes during de novo VH-to-DJH recombination that is more severe than the fetal liver (FL) B cell repertoire, and we now show a role for IL-7R signalling in DH-to-JH recombination. Transcriptome and accessibility analyses suggests reduced expression of B lineage-specific transcription factors (TFs) and their targets, and loss of DH and VH antisense transcription in IL-7R-/- B cells. These results refute models suggesting that IL-7R signalling is only required for survival and proliferation, and demonstrate a pivotal role in shaping the Igh repertoire by activating underpinning epigenetic mechanisms.

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Baizan Edge, A., Stubbs, B. A., Stubbington, M. J. T., Bolland, D. J., Tabbada, K., Andrews, S., Corcoran, A. E.. 2020-09-25. IL-7R signalling activates widespread VH and DH gene usage to drive antibody diversity in bone marrow B cells. https://doi.org/10.1101/2020.09.24.298000

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