Role of PD-1/PD-L1 in Acute and Chronic Graft Versus Host Disease

Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. PD-1 is an inhibitory receptor that attenuates TCR signaling.  Its expression is inducible on T-cells, B-cells, NKT-cells, and activated monoytes. Interactions between PD-1 and its ligands deliver inhibitory signals that regulate T-cell activation, tolerance, and immune-mediated tissue damage.  A blocking anti-PD-1 mAb given at the time of transplant markedly accelerated acute GVHD lethality in preclinical models via an interferon-gamma dependent mechanism. Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. PD-L2 expression was limited to hematopoietic cells, but hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. PD-L1-deficient hosts exhibit rapid mortality associated with increased gut T-cell homing and loss of intestinal epithelial integrity, increased donor T-cell proliferation, activation, Th1 cytokine production, and reduced apoptosis. Bioenergetics profile analysis of proliferating alloreactive donor T-cells demonstrated increased aerobic glycolysis and oxidative phosphorylation, hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter. During acute GVHD, PD-L1 was up-regulated on donor T-cells. Surprisingly, GVHD-induced lethality was significantly reduced in recipients of donor T cells devoid of PD-L1 and associated with reduced PD-L1^-/- donor T-cell infiltration into lymphoid organs and gut, a retention of intestinal epithelial integrity, and a lower production of inflammatory cytokines. During GVHD, PD-L1^-/- donor T cells showed increased apoptosis and reduced proliferation, as well as reduced glycolysis, glutaminolysis, and fatty acid metabolism. A role for PD-L1 in glucose-mediated acetyl-CoA production was seen, highlighting the important of glucose as an important carbon source in in alloreactive T cells undergoing clonal expansion. Further data support the hypothesis that the PD-1/PD-L1 pathway regulates T-T interaction. Together our studies indicate that PD-L1 expression that is upregulated on alloreactive donor T cells increases their survival and alters their metabolic pathway utilization in GVHD mice. In contrast to acute GVHD models, we have found that PD-1 pathway blockade can reduce chronic GVHD in a mouse model of multi-organ system disease in which one prominent component is bronchiolitis obliterans. This may occur via effects on T follicular regulatory or germinal center B cells. In summary, we have identified distinct consequences of PD-1/PD-L1 engagement in preclinical acute and chronic GVHD models: PD-1/PD-L1 interactions restrain acute GVHD but increase chronic GVHD. These findings illustrate the important but complex regulatory features of this pathway on a wide array of cell types. Our finding suggests PD-1 pathway modulation may provide unique opportunities for altering immune regulation post-transplant.