Immune cell compartmentalization and interactions in lymph nodes and spleen, with a focus on stromal fibroblasts

The architecture of secondary lymphoid organs is key to mount effective adaptive immunity and it depends on fibroblastic reticular cells (FRCs), which form niches guiding immune cell positioning. Yet, the molecular cues driving FRC subset differentiation remain unclear.

Upon identification of a Notch signaling signature within various FRC subsets we combined mouse genetics, transcriptomic profiling, flow cytometric analysis and microscopic imaging to dissect the importance of this pathway in lymph node (LN) FRCs. Notch2, targeted via CCL19-Cre, proved essential for postnatal development of CCL19hi T zone FRCs (TRCs) and their identity maintenance. These cells form a CCL19 gradient that organizes a central T zone enriched in CCR7⁺ CD8⁺ T cells and Xcr1⁺ cDC1s. This spatial organization and Notch activity in TRCs were found to be conserved in human LNs.

Mechanistically, homeostatic mature DCs, expressing high Jagged-1, activate Notch2 signaling in TRCs and drive their differentiation and CCL19 expression. Disruption of this loop impairs T zone structure and CD8⁺ T cell responses. CCL19 has a non-redundant role in establishing this niche (Alouche et al., Immunity 2026).

Unpublished data will also be presented on the role of Notch2 signaling in splenic fibroblast development and their role in B cell follicle versus T zone compartmentalization, along with its implication for adaptive immunity