Notch is a signal integrating hub that controls differentiation of effector CD8+ T cells (LYM7P.614)

Abstract

Abstract Activated CD8+ T-cells must choose between different effector cell fates. Two major fates are the short lived terminal effector cell (TEC) fate and the memory precursor cell (MPC) fate. Differentiation of immediately protective TECs is proportional to the severity of the infection, suggesting the existence of signals that relay information about the infection to promote the generation of this effector cell type. We here show that the choice between the TEC and MPC fates is governed by inductive signaling via Notch. This cell surface receptor promotes differentiation of TEC and is correspondingly required for clearance of influenza-virus infection. Notch activates a major portion of the TEC-specific gene expression program and suppresses the MPC-program, thus creating maximal separation between the two cell fates. Influenza infection induces ligands for Notch on lung derived migratory dendritic cells in mediastinal lymph nodes. Notch receptors are induced on naïve CD8+ T-cells by inflammatory mediators and IL-2 via mTOR and T-bet dependent pathways. These pathways are subsequently amplified downstream of Notch, thus creating a positive feedback loop to bolster full adoption of the TEC fate. Our results show that Notch functions as a central hub where signals from different sources of information converge and refuel to match effector T-cell differentiation to the demands of the infection.