Programmed death ligand-1 expression on donor T cells drives graft-versus-host disease lethality
| Autor: | Arlene H. Sharpe, Ian A. Blair, William J. Murphy, David H. Munn, Roddy S. O’Connor, Jonathan S. Serody, Catarina Sacristán, Govindarajan Thangavelu, Caleph B. Wilson, Gordon J. Freeman, Jan M. Pawlicki, Michael C. Milone, Bruce R. Blazar, Scott B. Lovitch, Asim Saha, Durga Bhavani Dandamudi, Rocio Foncea, James L. Riley, Laurence A. Turka, Kazutoshi Aoyama, Scott N. Furlan, Parvathi Ranganathan, Patricia A. Taylor, Brian T. Fife, David A. Bernlohr, Angela Panoskaltsis-Mortari, Benjamin G. Vincent, Leslie S. Kean, Joel S. Burrill, Lili Guo, Steven M. Devine, Victor Tkachev, Michael L. Dustin, Jeffrey S. Miller, Nathaniel W. Snyder |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
T-Lymphocytes Glutamine Programmed Cell Death 1 Receptor Graft vs Host Disease Apoptosis Inbred C57BL Medical and Health Sciences B7-H1 Antigen Interleukin 21 Mice 0302 clinical medicine Leukocytes Cytotoxic T cell 2.1 Biological and endogenous factors IL-2 receptor Phosphorylation Aetiology Inbred BALB C Bone Marrow Transplantation Cancer Mice Inbred BALB C General Medicine medicine.anatomical_structure Treatment Outcome Cytokines Female Stem Cell Research - Nonembryonic - Non-Human medicine.symptom Glycolysis Research Article Signal Transduction T cell Mononuclear Immunology Inflammation Bone Marrow Cells Biology 03 medical and health sciences Immune system Rare Diseases medicine Animals Humans Transplantation Inflammatory and immune system medicine.disease Stem Cell Research Mice Inbred C57BL Oxygen 030104 developmental biology Graft-versus-host disease Glucose Orphan Drug Leukocytes Mononuclear 030215 immunology |
| Zdroj: | The Journal of clinical investigation, vol 126, iss 7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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