Effector memory T cells (TEM) are less capable of inducing graft-versus-host disease (GVHD) compared with naive T cells (TN). Previously, in the TS1 TCR transgenic model of GVHD, wherein TS1 CD4 cells specific for a model minor histocompatibility Ag (miHA) induce GVHD in miHA-positive recipients, we found that cell-intrinsic properties of TS1 TEM reduced their GVHD potency relative to TS1 TN Posttransplant, TS1 TEM progeny expressed higher levels of PD-1 than did TS1 TN progeny, leading us to test the hypothesis that TEM induce less GVHD because of increased sensitivity to PD-ligands. In this study, we tested this hypothesis and found that indeed TS1 TEM induced more severe skin and liver GVHD in the absence of PD-ligands. However, lack of PD-ligands did not result in early weight loss and colon GVHD comparable to that induced by TS1 TN, indicating that additional pathways restrain alloreactive TEM TS1 TN also caused more severe GVHD without PD-ligands. The absence of PD-ligands on donor bone marrow was sufficient to augment GVHD caused by either TEM or TN, indicating that donor PD-ligand-expressing APCs critically regulate GVHD. In the absence of PD-ligands, both TS1 TEM and TN induced late-onset myocarditis. Surprisingly, this was an autoimmune manifestation, because its development required non-TS1 polyclonal CD8+ T cells. Myocarditis development also required donor bone marrow to be PD-ligand deficient, demonstrating the importance of donor APC regulatory function. In summary, PD-ligands suppress both miHA-directed GVHD and the development of alloimmunity-induced autoimmunity after allogeneic hematopoietic transplantation.