It Takes Three Receptors to Raise a B Cell.

As the unique source of diverse immunoglobulin repertoires, B lymphocytes are an indispensable part of humoral immunity. B cell progenitors progress through sequential and mutually exclusive states of proliferation and recombination, coordinated by cytokines and chemokines. Mutations affecting the crucial pre-B cell checkpoint result in immunodeficiency, autoimmunity, and leukemia. This checkpoint was previously modeled by the signaling of two opposing receptors, IL-7R and the pre-BCR. We provide an update to this model in which three receptors, IL-7R, pre-BCR, and CXCR4, work in concert to coordinate both the proper positioning of B cell progenitors in the bone marrow (BM) microenvironment and their progression through the pre-B checkpoint. Furthermore, signaling initiated by all three receptors directly instructs cell fate and developmental progression.