Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality

A Saha, K Aoyama, PA Taylor… - Blood, The Journal …, 2013 - ashpublications.org
A Saha, K Aoyama, PA Taylor, BH Koehn, RG Veenstra, A Panoskaltsis-Mortari, DH Munn…
Blood, The Journal of the American Society of Hematology, 2013ashpublications.org
Abstract Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important
role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in
regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were
upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression
was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1.
PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality …
Abstract
Programmed death 1 (PD-1) and its ligands, PD-L1 and PD-L2, play an important role in the maintenance of peripheral tolerance. We explored the role of PD-1 ligands in regulating graft-versus-host disease (GVHD). Both PD-L1 and PD-L2 expression were upregulated in the spleen, liver, colon, and ileum of GVHD mice. Whereas PD-L2 expression was limited to hematopoietic cells, hematopoietic and endothelial cells expressed PD-L1. PD-1/PD-L1, but not PD-1/PD-L2, blockade markedly accelerated GVHD-induced lethality. Chimera studies suggest that PD-L1 expression on host parenchymal cells is more critical than hematopoietic cells in regulating acute GVHD. Rapid mortality onset in PD-L1-deficient hosts was associated with increased gut T-cell homing and loss of intestinal epithelial integrity, along with 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 in PD-L1-deficient hosts. Donor T-cells exhibited a hyperpolarized mitochondrial membrane potential, increased superoxide production, and increased expression of a glucose transporter in PD-L1-deficient hosts. Taken together, these data provide new insight into the differential roles of host PD-L1 and PD-L2 and their associated cellular and metabolic mechanisms controlling acute GVHD.
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