Notch driven mTORC1 signaling enables rapid, division-independent plasma cell division in marginal zone B cells

Abstract

Lymphocyte differentiation is often tightly linked to mitosis. Clonal bursts due to antigen- or TLR-driven responses increase numbers of responding cells and may also facilitate changes in gene expression and chromatin needed for effector cell differentiation. Alternatively, to guard against rapid infection, lymphocyte pools may also contain cells poised for effector differentiation with minimal proliferation. Since marginal zone (MZ) B cells, which have increased basal mTORC1 activity and c-Myc expression, reside in the marginal sinus of the spleen where they are positioned to respond rapidly to blood borne microbes, we compared their ability to produce plasma cells (PC) with that of follicular B cells in an ex-vivo stimulation assay. We found that MZ B cells are able to produce PCs rapidly and independently of cell division whether exposed to cell cycle inhibitors or with genetic ablation of Cdk1. Furthermore, we found that blockade of Notch signaling rapidly down-regulated c-Myc-driven gene expression and mTORC1 activity in MZ B cells and caused them to adopt differentiation kinetics similar to follicular B cells. Genetic ablation of c-Myc further emphasized the uncoupling of cell division and differentiation in MZ B cells. Whereas acute loss of c-Myc blocked all cell division in ex-vivo stimulation assays, PC differentiation was only blocked with prolonged loss of c-Myc. Finally, using genetic ablation of Tsc1 to disinhibit mTORC1 signaling, we conferred both rapid and division-independent plasma cell differentiation to follicular B cells. These data illustrate that ongoing Notch signaling through c-Myc and mTORC1 allow for rapid division-independent antibody responses in MZ B cells.