Host Tissue PD-L1 Separates GVL Effect from Gvhd after Temporary Depletion of Donor CD4⁺ T Cells Early after HCT

Recipient tissue expression of programmed death-ligand 1 (PD-L1, B7H1) down-regulates graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT), but this information has not been translated clinically. Here we demonstrate a critical role for recipient PD-L1 expression in preventing both acute and chronic GVHD while preserving graft-versus-leukemia (GVL) effects when donor CD4⁺ T cells are temporarily depleted in vivo early after HCT. Depletion of donor CD4⁺ T cells increases serum IFN-γ concentrations and enhances recipient tissue expression of PD-L1 and donor CD8⁺ T cell expression of the PD-L1 receptors CD80 and PD-1. In GVHD target tissues, depletion of CD4⁺ T cells increases anergy and apoptosis of infiltrating CD8⁺ T cells in a manner that depends on recipient PD-L1 expression, thereby preventing damage to intestinal Paneth cells and stem cells, hepatocytes, and thymic medullary epithelial cells, and preventing both acute and chronic GVHD. In lymphoid tissues, depletion of CD4⁺ T cells augments CD8⁺ T cell proliferation without increasing CD8⁺ T cell anergy or apoptosis, resulting in expansion of donor CD8⁺ T cells and strong GVL effects. Therefore, temporary depletion of donor CD4⁺ T cells early after HCT represents a novel approach for preventing GVHD while preserving GVL effects. This work was supported by NIH R01 AI066008 and Nesvig Lymphoma Fundation (to D.Z.) and by NSFC 81090413, 81270638 (to J.W.).