Recipient Endothelial IRF1 Mediates IFNγ-Driven Tissue Tolerance in Mouse Models of Acute Graft-Versus-Host Disease
Researchers from The Ohio State University, with collaborators from Nationwide Children's Hospital, NYU Grossman Long Island School of Medicine, and Memorial Sloan Kettering Cancer Center, have identified recipient endothelial cells as active regulators of immune tolerance after allogeneic hematopoietic cell transplantation. Published in Blood, the study showed that interferon-γ (IFNγ) signaling through interferon regulatory factor 1 (IRF1) in lymphatic endothelial cells is required for donor regulatory T (Treg) cell expansion but dispensable for T helper 1 (Th1) expansion in mouse models of acute graft-versus-host disease (GVHD).
Endothelial injury has been repeatedly linked to adverse transplant outcomes, but the mechanisms separating endothelial support of tolerance from endothelial contribution to pathology remain incompletely defined. The investigators performed single-cell RNA sequencing on liver endothelial cells from syngeneic and allogeneic transplant recipients at days 4 and 14, neutralized IFNγ with monoclonal antibody at early (days -1 and 3) or late (days 9 and 13) time points, co-cultured stimulated lymphatic endothelial cells with mismatched naive CD4 T cells under JAK, MHC II, or PD-L1 blockade, and generated bone marrow chimeras in which IRF1 deficiency was restricted to the recipient non-hematopoietic compartment.
Allogeneic recipients showed induction of IFNγ-inducible genes in lymphatic endothelial cells, including Irf1, Ciita, and Cd274 (encoding PD-L1). Circulating IFNγ peaked at day 4, remained elevated at day 14, and declined by day 21, with concordant induction of IRF1+ lymphatic endothelial cells in the liver and gastrointestinal tract. Early IFNγ neutralization reduced endothelial activation without changing donor T cell counts, whereas late neutralization worsened clinical GVHD scores and accelerated mortality, reducing Tregs while leaving Th1 cells unchanged. In co-culture, JAK inhibition and PD-L1 blockade selectively impaired Treg expansion, while MHC II blockade reduced both subsets. Irf1-deficient chimeras showed reduced endothelial activation and apoptosis but fewer suppressive CD39hi Tregs, higher Th1/Treg ratios, and worse GVHD. Ruxolitinib reduced GVHD severity and improved survival while lowering Th1 numbers and preserving IRF1+ lymphatic endothelial cells and Tregs more than IFNγ neutralization or IRF1 deletion, with donor antitumor cytotoxicity retained. The authors conclude that endothelial IFNγ-IRF1 signaling requires calibration rather than ablation.
Reference:
Neidemire-Colley L, Kumar R, Garfinkle EA, et al. Recipient Endothelial IRF1 mediates IFNγ-driven tissue tolerance in mouse models of acute Graft-versus-Host Disease. Blood. Published online August 4, 2026. https:doi.org/10.1182/blood.2026033806