Department of Immunobiology, Yale University School of Medicine, Yale University, New Haven, CT.
Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO.
J Exp Med. 2018 Oct 1;215(10):2586-2599. doi: 10.1084/jem.20180778. Epub 2018 Aug 29.
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-7CXCL12 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.
B 细胞前体需要旁分泌信号，如骨髓基质细胞分泌的白细胞介素 7（IL-7），以进行增殖和存活。然而，B 细胞如何在体内调节对这些信号的获取仍不清楚。在这里，我们表明 proB 和 IL-7 细胞形成了一个由 IL-7R 信号转导连接的细胞回路，该信号转导控制 CXCR4 和粘着斑激酶（FAK）的表达，并由于与 IL-7CXCL12 细胞的粘附增加而限制 proB 细胞的运动。PreBCR 信号通过增加 CXCR4 和减少 FAK/α4β1 的表达，将 preB 细胞的行为切换为快速移动和低粘附状态，从而打破这个回路。这种行为上的改变减少了 preB 细胞对 IL-7 的暴露，从而减弱了体内的 IL-7R 信号转导。值得注意的是，未修复双链 DNA 断裂的 preB 细胞和 preB 急性淋巴细胞性白血病细胞提供的信号下调了 IL-7 的产生。综上所述，这些研究揭示了不同的细胞回路控制 B 细胞前体的质量和体内平衡。
