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 journalArticle

102 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 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.

Original languageEnglish (US)
Pages (from-to)3062-3073
Number of pages12
JournalBlood
Volume122
Issue number17
StatePublished - Oct 24 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology
  • Medicine(all)

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    Saha, A., Aoyama, K., Taylor, P. A., Koehn, B. H., Veenstra, R. G., Panoskaltsis-Mortari, A., Munn, D. H., Murphy, W. J., Azuma, M., Yagita, H., Fife, B. T., Sayegh, M. H., Najafian, N., Socie, G., Ahmed, R., Freeman, G. J., Sharpe, A. H., & Blazar, B. R. (2013). Host programmed death ligand 1 is dominant over programmed death ligand 2 expression in regulating graft-versus-host disease lethality. Blood, 122(17), 3062-3073.