Our results show that signaling from GVHD target tissue PD-L1 interaction with PD-1 on donor T cells inhibits GSH/Myc pathways and causes dysfunctional metabolic reprogramming in activated STAT3-deficient but not Mito-STAT3–deficient donor T cells, leading to anergy, exhaustion, and apoptosis of the STAT3-deficient T cells, thereby preventing GVHD. The gene discussed is PDCD1; the disease is graft versus host disease.