Endothelial IFNγ-IRF1 Signaling in GVHD
Neidemire-Colley L, Kumar R, Garfinkle EAR, et al. Recipient Endothelial IRF1 Mediates IFNγ-Driven Tissue Tolerance in Mouse Models of Acute Graft-Versus-Host Disease. Blood. 2026; (doi: 10.1182/blood.2026033806).
The endothelial interferon-γ-interferon regulatory factor 1 (IFNγ-IRF1) axis is implicated in the probability and severity of graft-versus-host disease (GVHD) following allogeneic hematopoietic cell transplantation (allo-HCT), researchers report. Post-procedure, lymphatic endothelial cells (ECs) located away from the liver, a vulnerable organ for GVHD, undergo rapid transcriptional reprogramming, including induction of interferon-γ-inducible genes like IRF1, MHC II, and PD-L1. The IFNγ-IRF1 axis is not required for T helper type 1 (Th1) cell expansion, but regulatory T cell (Treg) expansion relies on it. Therefore, ablating the recipient IFNγ-IRF1 axis selectively impairs donor Treg, worsening GVHD, as observed in murine models of allo-HCT. Recipient ECs unable to mediate IFNγ-IRF1 signaling are associated with elevated GVHD severity. Lab experiments also reveal that pharmacological JAK inhibition spares IRF1-positive lymphatic ECs and Tregs but reduces pathogenic Th1 cells, contributing to the desirable outcome of reduced GVHD severity and prolonged survival.