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

Asim Saha, Kazutoshi Aoyama, Patricia A. Taylor, Brent H. Koehn, Rachelle G. Veenstra, Angela Panoskaltsis-Mortari, David H. Munn, William J. Murphy, Miyuki Azuma, Hideo Yagita, Brian T. Fife, Mohammed H. Sayegh, Nader Najafian, Gerard Socie, Rafi Ahmed, Gordon J. Freeman, Arlene H. Sharpe, Bruce R. Blazar

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

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 andendothelial 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.

Original languageEnglish (US)
Pages (from-to)3062-3073
Number of pages12
JournalBlood
Volume122
Issue number17
DOIs
StatePublished - 2013

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