In this study, we found inhibited activation of CD4+ T cells and IFN-γ expression of allogeneic T cells in mice receiving Lyg1-/- donor T cells, whereas rhLYG1 administration aggravated aGVHD severity through promoting IFN-γ production of allogeneic T cells, more importantly, the absence of IFN-γ in donor T cells could partially abrogate rhLYG1-induced GVHD development, corroborating that the effect of LYG1 on aGVHD were mainly mediated by IFN-γ. This evidence concerns the gene CD4 and graft versus host disease.