The differential effects of IFN-γ on GVHD target organs and GVL. After conditioning induced tissue damage, NK and NKT cells are activated through activating receptor ligands (eg, NKG2D) and inhibitory receptors (eg, killer inhibitory receptors [KIR]) and TCR ligation (in the case of NKT cells), resulting in rapid IFN-γ release and licensing of recipient APCs (ie, up-regulation of CD40 and CD80/86). Transplanted donor T cells are activated after interaction with these host APCs to undergo expansion and Th1/Tc1 differentiation. IFN-γ production by donor T cells augments gut damage via (1) promoting Th1 and Tc1 differentiation and subsequent cytolysis against target tissue (eg, via perforin/granzyme), (2) direct cytopathic effects of the cytokine itself on the GI tract, and (3) priming monocytes/macrophages such that they secrete quantities of TNF and lymphotoxin after signaling by TLR ligands that are themselves directly cytopathic to the GI tract. In contrast to these pathogenic effects, IFN-γ secretion by donor T cells is critical in the lung parenchyma to induce PDL1 expression, which subsequently inhibits donor T-cell survival and infiltration within this organ, preventing the development of idiopathic pneumonia syndrome (IPS). IFN-γ also promotes GVL effects via (1) the enhancement of CTL expansion and function (eg, perforin/granzyme-dependent killing) and (2) acting on leukemia cells directly (eg, to up-regulate MHC expression and death receptors), rendering them more susceptible to T cell–mediated cytolysis.