Homeostatic mature dendritic cells instruct fibroblast specialization via Notch2 signaling to establish T cell niches.

Compartmentalization of secondary lymphoid organs is orchestrated by specialized fibroblastic reticular cells (FRCs), which guide immune cell migration, interaction, and function. Here, we investigated the pathways driving FRC differentiation into functionally distinct subsets. A Notch signaling signature distinguished lymph node (LN) FRCs, and deletion of Notch1 and Notch2 in FRCs restricted functional specialization, particularly for T-zone FRCs (T-zone reticular cells [TRCs]). Dendritic cell (DC)-specific deletion of the Notch ligand Jagged-1 prevented Ccl19hi TRC differentiation, with homeostatic Ccr7+ DCs also being required for their maintenance. The resulting Ccl19 chemokine expression supported formation of central T-zone sub-compartments enriched in Xcr1+ DCs and CD8+ T cells. Both the spatial organization and Notch2-Jagged1 signaling activity were conserved in human LNs. Disrupting T-zone segregation via Notch2 inactivation in FRCs impaired the generation of CD8+ T cell memory precursors. Thus, Notch2-dependent TRC programming by DCs shapes distinct T-zone niches that sustain CD8+ T cell immunity.