PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells.

Autor: Stathopoulou C; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Gangaplara A; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Mallett G; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Flomerfelt FA; Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Liniany LP; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Knight D; Biological Mass Spectrometry Core, University of Manchester, Manchester M13 9PL, UK., Samsel LA; Flow Cytometry Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA., Berlinguer-Palmini R; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK., Yim JJ; School of Medicine, Stanford University, Stanford, CA 94305, USA., Felizardo TC; Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA., Eckhaus MA; Division of Veterinary Resources, Office of Research Services, NIH, Bethesda, MD 20892, USA., Edgington-Mitchell L; School of Medicine, Stanford University, Stanford, CA 94305, USA; Drug Discovery Biology, Monash University, Melbourne, VIC 3800, Australia., Martinez-Fabregas J; College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK., Zhu J; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Fowler DH; Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA., van Kasteren SI; Leiden Institute of Chemistry and Institute of Chemical Immunology, Leiden University, 2311 EZ Leiden, the Netherlands., Laurence A; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Translational Gastroenterology Unit, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Headington, Oxford OX3 9DU, UK; Department of Haematology, Northern Centre for Cancer Care, Newcastle upon Tyne NE2 4HH, UK., Bogyo M; School of Medicine, Stanford University, Stanford, CA 94305, USA., Watts C; College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK., Shevach EM; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA., Amarnath S; Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: shoba.amarnath@newcastle.ac.uk.
Jazyk: angličtina
Zdroj: Immunity [Immunity] 2018 Aug 21; Vol. 49 (2), pp. 247-263.e7. Date of Electronic Publication: 2018 Jul 24.
DOI: 10.1016/j.immuni.2018.05.006
Abstrakt: CD4 + T cell differentiation into multiple T helper (Th) cell lineages is critical for optimal adaptive immune responses. This report identifies an intrinsic mechanism by which programmed death-1 receptor (PD-1) signaling imparted regulatory phenotype to Foxp3 + Th1 cells (denoted as Tbet + iTreg PDL1 cells) and inducible regulatory T (iTreg) cells. Tbet + iTreg PDL1 cells prevented inflammation in murine models of experimental colitis and experimental graft versus host disease (GvHD). Programmed death ligand-1 (PDL-1) binding to PD-1 imparted regulatory function to Tbet + iTreg PDL1 cells and iTreg cells by specifically downregulating endo-lysosomal protease asparaginyl endopeptidase (AEP). AEP regulated Foxp3 stability and blocking AEP imparted regulatory function in Tbet + iTreg cells. Also, Aep -/- iTreg cells significantly inhibited GvHD and maintained Foxp3 expression. PD-1-mediated Foxp3 maintenance in Tbet + Th1 cells occurred both in tumor infiltrating lymphocytes (TILs) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway.
(Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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