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Abstract

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. Previous studies have shown that receptor editing is the predominant central tolerance mechanism for self-reactive B cells in the bone marrow. Receptor editing rescues autoreactive B cells from negative selection, by inducing renewed light chain recombination first at Igk then Igl loci. Reports have indicated the lambda-chain has distinct physiochemical properties that are particularly effective at quenching autoreactivity to DNA; yet, molecular mechanism of receptor editing that lead to the usage of the lambda-chain remain ill defined. Herein, we elucidate transcriptional and epigenetic features of receptor editing cells and show chemokine receptor CXCR4 is essential for maintaining the editing state and orchestrating Igl light recombination. Editing small pre-B cells possess unique open chromatin regions enriched for E2A and NF-kB, key regulators of Igl recombination and receptor editing. These regions showed evidence of having been acquired by partial differentiation into the immature B cell stage. Transcriptionally, editing cells showed upregulation of oxidative phosphorylation, DNA repair mechanisms and CXCR4. CXCR4 deficiency in autoreactive B cells showed a selective defect in Igl recombination and tolerance induction, suggesting CXCR4 is necessary for the differentiation of Igl+ B cells during receptor editing.

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