Asymmetrical forward and reverse developmental trajectories determine molecular programs of B cell antigen receptor editing

During B lymphopoiesis, B cell progenitors progress through alternating and mutually exclusive stages of clonal expansion and immunoglobulin (Ig) gene rearrangements. Great diversity is generated through the stochastic recombination of Ig gene segments encoding heavy and light chain variable domains...

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Bibliographic Details
Published in:	Science immunology Vol. 7; no. 74; p. eabm1664
Main Authors:	Okoreeh, Michael K, Kennedy, Domenick E, Emmanuel, Akinola Olumide, Veselits, Margaret, Moshin, Azam, Ladd, Robert H, Erickson, Steven, McLean, Kaitlin C, Madrigal, Brianna, Nemazee, David, Maienschein-Cline, Mark, Mandal, Malay, Clark, Marcus R
Format:	Journal Article
Language:	English
Published:	United States 05-08-2022
Subjects:	Animals B-Lymphocytes Chromatin - metabolism Mice Receptors, Antigen, B-Cell - genetics Recombination, Genetic Transcription Factors - genetics
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Summary:	During B lymphopoiesis, B cell progenitors progress through alternating and mutually exclusive stages of clonal expansion and immunoglobulin (Ig) gene rearrangements. Great diversity is generated through the stochastic recombination of Ig gene segments encoding heavy and light chain variable domains. However, this commonly generates autoreactivity. Receptor editing is the predominant tolerance mechanism for self-reactive B cells in the bone marrow (BM). B cell receptor editing rescues autoreactive B cells from negative selection through renewed light chain recombination first at κ then λ loci. Receptor editing depends on BM microenvironment cues and key transcription factors such as NF-κB, FOXO, and E2A. The specific BM factor required for receptor editing is unknown. Furthermore, how transcription factors coordinate these developmental programs to promote usage of the λ chain remains poorly defined. Therefore, we used two mouse models that recapitulate pathways by which Igλ light chain-positive B cells develop. The first has deleted J kappa (Jκ) genes and hence models Igλ expression resulting from failed κ recombination (Igκ ). The second models autoreactivity by ubiquitous expression of a single-chain chimeric anti-Igκ antibody (κ-mac). Here, we demonstrated that autoreactive B cells transit asymmetric forward and reverse developmental trajectories. This imparted a unique epigenetic landscape on small pre-B cells, which opened chromatin to transcription factors essential for λ recombination. The consequences of this asymmetric developmental path were both amplified and complemented by CXCR4 signaling. These findings reveal how intrinsic molecular programs integrate with extrinsic signals to drive receptor editing.
ISSN:	2470-9468
DOI:	10.1126/sciimmunol.abm1664