Stroma-derived Notch signals drive transdifferentiation of follicular B cells into marginal zone B cells during lymphopenia

Abstract

Abstract In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain poorly understood. To evaluate the homeostasis of the mature B cell pool during lymphopenia, we developed an adoptive transfer model of follicular B (FoB) cells into Rag2−/− mouse recipients. We report that highly purified FoB cells transdifferentiate into marginal zone (MZ)-like B cells when transferred into Rag2−/− lymphopenic hosts, but not into wild type hosts. In lymphopenic spleens, transferred B cells gradually lost their FoB phenotype and acquired multiple characteristics of MZ B cells, as judged by their cell surface phenotype (sIgMhi sIgDlow CD21hi CD1dhi CD23low), expression of integrins and chemokine receptors, positioning close to the marginal sinus, and functional ability to rapidly generate plasma cells. Initiation of FoB to MZ B cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B cells and expression of Delta-like 1 Notch ligands by Ccl19-Cre+ fibroblastic stromal cells, a pathway also required for MZ B cell development in steady-state conditions. We postulate that stromal Notch ligands are critical to regulate the size and composition of the splenic B cell pool via interactions with Notch2 receptors in B cells. Thus, FoB cells are not locked in their FoB cell fate, but are are endowed with plastic transdifferentiation potential in response to increased stromal Dll1 availability in lymphopenic environments.