The Notch-Myc signaling axis sets the division-differentiation clock in marginal zone B cells

Abstract

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. Using cell cycle inhibitors or induced mutation of CDK1, we directly compared the impact of arresting mitosis on early plasma cell (PC) differentiation for naive follicular and marginal zone (MZ) B cells. MZ B cells reside in the marginal sinus of the spleen where they are positioned to respond rapidly to blood borne microbes. Whereas PC differentiation from follicular B cells occurred after only 4 or more divisions and was highly dependent on mitosis, MZ B cells yielded PCs much faster and despite full cell cycle blockade. Furthermore, short-term withdrawal of Notch signaling in MZ B cells in vivo caused rapid and robust down-regulation of large numbers of established Myc-regulated genes, and resulted in division/differentiation kinetics that mirrored follicular B cells. Altogether these results suggest that ongoing Notch signaling establishes a differentiation-poised state in MZ B cells needed for rapid division-independent antibody responses.