Graft-versus-host disease (GVHD) is a lethal complication of allogeneic hematopoietic stem cell transplantation where activated donor T cells attack the genetically disparate host cells. The main target organs of the T cells in GVHD are the skin, liver, and intestine. In order to explain why the lung, one of the barrier organs, is spared from the injury of effector T cells, we hypothesize that endothelial cells are essential for immune regulation in acute GVHD. The proposed mechanism including Th1 cells apoptosis induced by endothelial cells expressing Tim-3 ligand galectin-9, and differential expression levels of galectin-9 on endothelial cells in various organs. The elucidation of the detailed cellular and molecular mechanisms that involved may help to a better understanding of immunoregulation in acute GVHD. Furthermore, the hypothesis may offer improved insight into new therapeutic strategy to reduce the severity of GVHD.