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Asymmetrical forward and reverse developmental trajectories determine molecular programs of B cell antigen receptor
Michael K Okoreeh1,2,3, Domenick E Kennedy1,2, Akinola Olumide Emmanuel1,2
1Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Science Immunology
|August 5, 2022
Summary
Self-reactive B cells undergo receptor editing in the bone marrow to avoid elimination. This process involves asymmetric developmental trajectories and epigenetic changes, enabling immunoglobulin lambda (Igλ) gene recombination.
Area of Science:
- Immunology
- Developmental Biology
- Molecular Biology
Background:
- B cell development generates diverse antibody repertoires through immunoglobulin (Ig) gene rearrangement.
- Autoreactive B cells, a common outcome of Ig gene rearrangement, are primarily eliminated by receptor editing in the bone marrow (BM).
- Receptor editing rescues self-reactive B cells via renewed light chain gene recombination, influenced by BM microenvironment cues and transcription factors.
Purpose of the Study:
- To investigate the specific BM factors and molecular mechanisms governing receptor editing, particularly the switch to Igλ light chain recombination.
- To elucidate how transcription factors coordinate B cell development and promote Igλ usage during receptor editing.
- To understand the interplay between intrinsic molecular programs and extrinsic signals in driving receptor editing.
Main Methods:
- Utilized two mouse models: Igκ-deleted (Igκdel) mice mimicking failed Igκ recombination and κ-mac mice modeling autoreactivity.
- Analyzed the developmental trajectories and epigenetic landscapes of autoreactive B cells during receptor editing.
- Investigated the role of CXCR4 signaling in amplifying and complementing receptor editing pathways.
Main Results:
- Autoreactive B cells exhibit asymmetric developmental trajectories, involving both forward and reverse pathways.
- This asymmetric development creates a unique epigenetic landscape in small pre-B cells, facilitating Igλ gene recombination.
- CXCR4 signaling amplifies and complements the effects of these asymmetric developmental paths.
Conclusions:
- Receptor editing involves complex, asymmetric developmental trajectories that alter the epigenetic state of B cell progenitors.
- These intrinsic molecular programs, integrated with extrinsic signals like CXCR4, are crucial for rescuing autoreactive B cells and promoting Igλ recombination.
- The study reveals novel insights into the coordination of transcription factors and signaling pathways in B cell tolerance.
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