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J Exp Med. 2018 Oct 1;215(10):2586-2599. doi: 10.1084/jem.20180778. Epub 2018 Aug 29.

Cell circuits between B cell progenitors and IL-7+ mesenchymal progenitor cells control B cell development.

Author information

1
Department of Immunobiology, Yale University School of Medicine, Yale University, New Haven, CT.
2
Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO.
3
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY.
5
Department of Immunobiology, Yale University School of Medicine, Yale University, New Haven, CT Joao.Pereira@yale.edu.

Abstract

B cell progenitors require paracrine signals such as interleukin-7 (IL-7) provided by bone marrow stromal cells for proliferation and survival. Yet, how B cells regulate access to these signals in vivo remains unclear. Here we show that proB and IL-7+ cells form a cell circuit wired by IL-7R signaling, which controls CXCR4 and focal adhesion kinase (FAK) expression and restricts proB cell movement due to increased adhesion to IL-7+CXCL12Hi cells. PreBCR signaling breaks this circuit by switching the preB cell behavior into a fast-moving and lower-adhesion state via increased CXCR4 and reduced FAK/α4β1 expression. This behavioral change reduces preB cell exposure to IL-7, thereby attenuating IL-7R signaling in vivo. Remarkably, IL-7 production is downregulated by signals provided by preB cells with unrepaired double-stranded DNA breaks and by preB acute lymphoblastic leukemic cells. Combined, these studies revealed that distinct cell circuits control the quality and homeostasis of B cell progenitors.

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