Recipient Endothelial IRF1 mediates IFNgamma-driven tissue tolerance in acute Graft-versus-Host Disease

However, mechanisms via which non-hematopoietic host tissues actively shape post-transplant outcomes remains incompletely defined. Here, we identify endothelial cell (EC)-intrinsic interferon-g (IFNg)—IRF1 signaling as a key pathway controlling vascular remodeling and immune tolerance after allo-HCT.

Using single cell RNA sequencing of liver ECs from syngeneic and allogeneic transplant recipients, we reveal that liver ECs undergo rapid, subset-specific transcriptional reprogramming after allo-HCT, marked by strong induction of IFNg-responsive pathways. We show IRF1 is a key upstream regulator, linking IFNg signaling to endothelial activation and functional remodeling. Both in vitro and in vivo studies reveal that endothelial intrinsic IFNg—IRF1 signaling is dispensable for Th1 differentiation but required for endothelial-driven Treg expansion.