CXCR4 signaling directs Igk recombination and the molecular mechanisms of late B lymphopoiesis

In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet, how the pre-BCR mediates these functions remains unclear. Herein, we demonstrate that the pre-BCR initiated a feed-forward amplification loop mediated by the transcription factor IRF4 and the chemokine receptor CXCR4. CXCR4 ligation by CXCL12 activated the mitogen-activated protein kinase (MAPK) ERK which then directed the development of small pre- and immature B cells including orchestrating cell cycle exit, pre-BCR repression, Igk recombination and BCR expression. In contrast, pre-BCR expression and escape from interleukin 7 (IL-7) had only modest effects on B cell developmental transcriptional and epigenetic programs. These data demonstrate a direct and central role for CXCR4 in orchestrating late B cell lymphopoiesis. Furthermore, in the context of previous findings, our data provide a three-receptor system sufficient to recapitulate the essential features of B lymphopoiesis in vitro.