TY - JOUR
T1 - Cell circuits between B cell progenitors and IL-7+mesenchymal progenitor cells control B cell development
AU - Fistonich, Chris
AU - Zehentmeier, Sandra
AU - Bednarski, Jeffrey J.
AU - Miao, Runfeng
AU - Schjerven, Hilde
AU - Sleckman, Barry P.
AU - Pereira, João P.
N1 - Funding Information:
C. Fistonich was funded by the National Institutes of Health (T32 AI007019); S. Zehentmeier was funded by the German Research Foundation (DFG ZE1060/1-1). This work was funded by the National Institutes of Health (RO1AI113040 to J.P. Pereira). The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Fistonich et al.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85054054479&partnerID=8YFLogxK
U2 - 10.1084/JEM.20180778
DO - 10.1084/JEM.20180778
M3 - Article
C2 - 30158115
AN - SCOPUS:85054054479
SN - 0022-1007
VL - 215
SP - 2586
EP - 2599
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
ER -