Regulation of GVHD and GVL Activity via PD-L1 Interaction With PD-1 and CD80

Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies (i.e. leukemia and lymphoma), because graft-versus-leukemia (GVL) activity mediated by alloreactive T cells can eliminate residualmalignant cells and prevent relapse. However, the same alloreactive T cells alsomediate a severe side effect, graft-versus-host disease (GVHD), and prevention of GVHD while preserving GVL activity remains an elusive goal. The immune checkpoint molecule PD-L1 and its interaction with PD-1 receptor in regulating cancer immunity is under intensive and wide-spread study, but knowledge about this interaction in regulating GVHD and GVL activity is very limited. In this review, we summarize the literature exploring how PD-L1 interaction with its receptors PD-1 and CD80 regulate GVHD and GVL activities, how PD-L1 signaling regulates T cell metabolic profiles, and how a differential role of PD-L1 interaction with PD-1, CD80 or both may provide a novel avenue to prevent GVHD while preserving strong GVL effects.