GVL mediated by CD4⁺ T_EMs is intact when killing by FasL, TNF, TRAIL, and perforin is individually blocked, but is reduced when killing by both FasL and perforin is prevented. B6 mice were irradiated and reconstituted with T cell–depleted B6^bm12 BM, mCP-CML derived from wt, Fas^lpr, or TNFR1R2^−/− B6 mice (A,C,D) or TRAILR^−/− or TRAILR^+/+ littermates (B; data from 1 of 2 similar experiments), with no T cells, CD4⁺ T_Ns, or CD4⁺ T_EMs from wt or perforin^−/− B6^bm12 mice. Survival curves are plotted (A-E). The strains from which donor T cells and mCP-CML were derived are noted above each graph. When individually blocked, killing via TNFR1/R2 (A; P > .21 for recipients of wt T_EMs or T_Ns and TNFR1R2^−/− mCP-CML versus wt mCP-CML), TRAILR (B; P > .12 for recipients of wt T_EMs or T_Ns and TRAILR^−/− mCP-CML versus TRAILR^+/+ mCP-CML), Fas (C; P > .63 for recipients of wt T_EMs or T_Ns and Fas^lpr mCP-CML versus wt mCP-CML), or perforin (D; P > .47 for recipients of wt mCP-CML and Prf1^−/− versus wt T_Ns or T_EMs) is not required for GVL by either CD4⁺ T_Ns or T_EMs. However, when killing via both perforin and Fas was prevented (E), GVL by T_EMs but not T_Ns was diminished (P = .03 comparing recipients of CD4⁺Prf1^−/− T_EMs and wt mCP-CML versus CD4⁺Prf1^−/− T_EMs and Fas^lpr mCP-CML; P = .01 for recipients of Fas^lpr mCP-CML and no T cells versus Fas^lpr mCP-CML and CD4⁺Prf1^−/− T_EMs; P = .71 for recipients of CD4⁺Prf1^−/− T_Ns and wt mCP-CML versus CD4⁺Prf1^−/− T_Ns and Fas^lpr mCP-CML). Survival plots in panels C-E are from data combined from 2 independent experiments.