Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality

Asim Saha, Roddy S. O'Connor, Govindarajan Thangavelu, Scott B. Lovitch, Durga Bhavani Dandamudi, Caleph B. Wilson, Benjamin G. Vincent, Victor Tkachev, Jan M. Pawlicki, Scott N. Furlan, Leslie S. Kean, Kazutoshi Aoyama, Patricia A. Taylor, Angela Panoskaltsis-Mortari, Rocio Foncea, Parvathi Ranganathan, Steven M. Devine, Joel S. Burrill, Lili Guo, Catarina SacristanNathaniel W. Snyder, Ian A. Blair, Michael C. Milone, Michael L. Dustin, James L. Riley, David A. Bernlohr, William J Murphy, Brian T. Fife, David H. Munn, Jeffrey S. Miller, Jonathan S. Serody, Gordon J. Freeman, Arlene H. Sharpe, Laurence A. Turka, Bruce R. Blazar

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Programmed death ligand-1 (PD-L1) interaction with PD-1 induces T cell exhaustion and is a therapeutic target to enhance immune responses against cancer and chronic infections. In murine bone marrow transplant models, PD-L1 expression on host target tissues reduces the incidence of graft-versus-host disease (GVHD). PD-L1 is also expressed on T cells; however, it is unclear whether PD-L1 on this population influences immune function. Here, we examined the effects of PD-L1 modulation of T cell function in GVHD. In patients with severe GVHD, PD-L1 expression was increased on donor T cells. Compared with mice that received WT T cells, GVHD was reduced in animals that received T cells from Pdl1-/- donors. PD-L1-deficient T cells had reduced expression of gut homing receptors, diminished production of inflammatory cytokines, and enhanced rates of apoptosis. Moreover, multiple bioenergetic pathways, including aerobic glycolysis, oxidative phosphorylation, and fatty acid metabolism, were also reduced in T cells lacking PD-L1. Finally, the reduction of acute GVHD lethality in mice that received Pdl1-/- donor cells did not affect graft-versus-leukemia responses. These data demonstrate that PD-L1 selectively enhances T cell-mediated immune responses, suggesting a context-dependent function of the PD-1/PD-L1 axis, and suggest selective inhibition of PD-L1 on donor T cells as a potential strategy to prevent or ameliorate GVHD.

Original languageEnglish (US)
Pages (from-to)2642-2660
Number of pages19
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016

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ASJC Scopus subject areas

  • Medicine(all)

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Saha, A., O'Connor, R. S., Thangavelu, G., Lovitch, S. B., Dandamudi, D. B., Wilson, C. B., Vincent, B. G., Tkachev, V., Pawlicki, J. M., Furlan, S. N., Kean, L. S., Aoyama, K., Taylor, P. A., Panoskaltsis-Mortari, A., Foncea, R., Ranganathan, P., Devine, S. M., Burrill, J. S., Guo, L., ... Blazar, B. R. (2016). Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality. Journal of Clinical Investigation, 126(7), 2642-2660. https://doi.org/10.1172/JCI85796