Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative treatment for a variety of hematologic malignancies due to the well-recognized graft-versus-leukemia/lymphoma (GVL) effect that is mediated by donor-derived alloreactive T cells. However, graft-versus-host disease (GVHD) is mediated by the same T cells and remains a significant clinical problem associated with substantial morbidity and mortality. In this issue of the JCI, Ni and colleagues used several murine models of GVHD to evaluate the effect of CD4+ T cell depletion on GVL versus GVHD and revealed that depletion of CD4+ T cells leads to the upregulation of PD-L1 by recipient tissues and donor CD8+ T cells. Interaction of PD-L1 with PD-1 in GVHD-targeted tissues resulted in CD8+ T cell exhaustion and apoptosis, thereby preventing GVHD, whereas PD-L1 interactions with CD80 in lymphoid tissue promoted CD8+ T cell survival and expansion, thereby enhancing the GVL response. By separating these seemingly similar alloreactive T cell responses based on the context of interaction, the results of this study may lay the groundwork for the development of effective clinical strategies to enhance GVL while minimizing GVHD following allogeneic HCT.