@article {542096, title = {Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality.}, journal = {Blood}, volume = {122}, number = {17}, year = {2013}, month = {2013 Oct 24}, pages = {3062-73}, 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.}, keywords = {Acute Disease, Animals, Antigens, CD274, Apoptosis Regulatory Proteins, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes, Cell Proliferation, Gene Expression Regulation, Glucose Transport Proteins, Facilitative, Glycolysis, Graft vs Host Disease, Intestines, Liver, Mice, Oxidative Phosphorylation, Peripheral Tolerance, Programmed Cell Death 1 Ligand 2 Protein, Programmed Cell Death 1 Receptor, Spleen, Survival Analysis, Transplantation Tolerance}, issn = {1528-0020}, doi = {10.1182/blood-2013-05-500801}, author = {Saha, Asim and Aoyama, Kazutoshi and Taylor, Patricia A and Koehn, Brent H and Veenstra, Rachelle G and Panoskaltsis-Mortari, Angela and Munn, David H and Murphy, William J and Azuma, Miyuki and Yagita, Hideo and Fife, Brian T and Sayegh, Mohammed H and Najafian, Nader and Socie, Gerard and Ahmed, Rafi and Freeman, Gordon J and Sharpe, Arlene H and Blazar, Bruce R} }