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

Malay Mandal, Michael K. Okoreeh, Domenick E. Kennedy, Mark Maienschein-Cline, Junting Ai, Kaitlin C. McLean, Natalya Kaverina, Margaret Veselits, Iannis Aifantis, Fotini Gounari, Marcus R. Clark

Research output: Contribution to journalArticlepeer-review


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. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4). CXCR4 ligation by C-X-C motif chemokine ligand 12 activates the mitogen-activated protein kinase extracellular-signal-regulated kinase, which then directs 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 have only modest effects on B cell developmental transcriptional and epigenetic programs. These data show 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.

Original languageEnglish (US)
Pages (from-to)1393-1403
Number of pages11
JournalNature immunology
Issue number10
StatePublished - Oct 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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