Journal article
Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
The Journal of clinical investigation, v 126(7), pp 2642-2660
01 Jul 2016
PMID: 27294527
Featured in Collection : UN Sustainable Development Goals @ Drexel
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.
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Details
- Title
- Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
- Creators
- Asim Saha - University of Minnesota‐Twin CitiesRoddy S. O'Connor - Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USAGovindarajan Thangavelu - University of Minnesota‐Twin CitiesScott B. Lovitch - Harvard University ,Durga Bhavani Dandamudi - New York UniversityCaleph B. Wilson - University of PennsylvaniaBenjamin G. Vincent - University of North Carolina at Chapel HillVictor Tkachev - University of WashingtonJan M. Pawlicki - University of PennsylvaniaScott N. Furlan - University of WashingtonLeslie S. Kean - University of WashingtonKazutoshi Aoyama - University of Minnesota‐Twin CitiesPatricia A. Taylor - University of Minnesota‐Twin CitiesAngela Panoskaltsis-Mortari - University of Minnesota‐Twin CitiesRocio Foncea - University of Minnesota‐Twin CitiesParvathi Ranganathan - The Ohio State UniversitySteven M. Devine - The Ohio State UniversityJoel S. Burrill - University of Minnesota‐Twin CitiesLili Guo - University of PennsylvaniaCatarina Sacristan - New York UniversityNathaniel W. Snyder - Drexel UniversityIan A. Blair - University of PennsylvaniaMichael C. Milone - University of PennsylvaniaMichael L. Dustin - New York UniversityJames L. Riley - University of PennsylvaniaDavid A. Bernlohr - University of Minnesota‐Twin CitiesWilliam J. Murphy - University of California, DavisBrian T. Fife - University of Minnesota‐Twin CitiesDavid H. Munn - Prevention InstituteJeffrey S. Miller - University of Minnesota‐Twin CitiesJonathan S. Serody - University of North Carolina at Chapel HillGordon J. Freeman - Harvard University ,Arlene H. Sharpe - Harvard University ,Laurence A. Turka - Harvard University ,Bruce R. Blazer - Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA
- Publication Details
- The Journal of clinical investigation, v 126(7), pp 2642-2660
- Publisher
- Amer Soc Clinical Investigation Inc
- Number of pages
- 19
- Grant note
- R01AI034495 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID) Wellcome Trust; European Commission HL056067; AI034495; AI056299; AI043542 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA016086 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R37HL056067 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- A.J. Drexel Autism Institute
- Web of Science ID
- WOS:000379094800027
- Scopus ID
- 2-s2.0-84978399786
- Other Identifier
- 991019167965704721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Medicine, Research & Experimental