Coordination of YAP/TAZ Activity and Lymphotoxin-β Receptor Signaling Governs Maturation and Integrity of Fibroblastic Reticular Cells in Lymph Nodes

Fibroblastic reticular cells (FRCs) serve as a scaffolding microarchitecture for lymph nodes (LNs) and respond dynamically to various stimuli. However, the regulatory signaling pathways that govern the structural and functional adaptations of FRCs are poorly understood. Here, we show that YAP and TAZ, the end effectors of Hippo signaling, are dominant regulators of maturation and maintenance of FRCs. Constant or inducible genetic deletion or hyperactivation of YAP/TAZ led to impaired differentiation and maintenance of FRCs to varying degrees, leading to disrupted formation and compartmentalization of LNs and their immune responsiveness. Activation of LTβR signaling facilitated binding of p52 to YAP/TAZ and suppressed their transcriptional activities. Intriguingly, double deletion of YAP/TAZ and LTβR signaling transformed FRCs into adipocytes. Thus, LTβR signaling acts as a regulator of YAP/TAZ in FRCs. Accordingly, reduced LTβR signaling in the LNs harboring metastatic tumor promoted YAP/TAZ activity, leading to LN fibrosis and reduced anti-cancer immunity.