Splenic fibroblasts control marginal zone B cell movement and function via two distinct Notch2-dependent regulatory programs.

Innate-like splenic marginal zone (MZ) B (MZB) cells play unique roles in immunity due to their rapid responsiveness to blood-borne microbes. How MZB cells integrate cell-extrinsic and -intrinsic processes to achieve accelerated responsiveness is unclear. We found that Delta-like1 (Dll1) Notch ligands in splenic fibroblasts regulated MZB cell pool size, migration, and function.

Regulation of immune cell development, differentiation and function by stromal Notch ligands.

In multicellular organisms, cell-to-cell communication is critical for the regulation of tissue organization. Notch signaling relies on direct interactions between Notch receptors on signal-receiving cells and Notch ligands on adjacent cells. Notch evolved to mediate local cellular interactions that are responsive to spatial cues via dosage-sensitive short-lived signals.

Notch signaling drives intestinal graft-versus-host disease in mice and nonhuman primates.

Notch signaling promotes T cell pathogenicity and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT) in mice, with a dominant role for the Delta-like Notch ligand DLL4. To assess whether Notch's effects are evolutionarily conserved and to identify the mechanisms of Notch signaling inhibition, we studied antibody-mediated DLL4 blockade in a nonhuman primate (NHP) model similar to human allo-HCT. Short-term DLL4 blockade improved posttransplant survival with durable protection from gastrointestinal GVHD in particular.