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

Chaido Stathopoulou; Arunakumar Gangaplara; Grace Mallett; Francis A Flomerfelt; Lukasz P Liniany; David Knight; Leigh A Samsel; Rolando Berlinguer-Palmini; Joshua J Yim; Tania C Felizardo; Michael A Eckhaus; Laura Edgington-Mitchell; Jonathan Martinez-Fabregas; Jinfang Zhu; Daniel H Fowler; Sander I van Kasteren; Arian Laurence; Matthew Bogyo; Colin Watts; Ethan M Shevach; Shoba Amarnath

doi:10.1016/j.immuni.2018.05.006

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

Immunity. 2018 Aug 21;49(2):247-263.e7. doi: 10.1016/j.immuni.2018.05.006. Epub 2018 Jul 24.

Authors

Chaido Stathopoulou¹, Arunakumar Gangaplara², Grace Mallett¹, Francis A Flomerfelt³, Lukasz P Liniany¹, David Knight⁴, Leigh A Samsel⁵, Rolando Berlinguer-Palmini¹, Joshua J Yim⁶, Tania C Felizardo³, Michael A Eckhaus⁷, Laura Edgington-Mitchell⁸, Jonathan Martinez-Fabregas⁹, Jinfang Zhu², Daniel H Fowler³, Sander I van Kasteren¹⁰, Arian Laurence¹¹, Matthew Bogyo⁶, Colin Watts⁹, Ethan M Shevach², Shoba Amarnath¹²

Affiliations

¹ Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
² Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
³ Experimental Transplantation Immunology Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
⁴ Biological Mass Spectrometry Core, University of Manchester, Manchester M13 9PL, UK.
⁵ Flow Cytometry Core, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892, USA.
⁶ School of Medicine, Stanford University, Stanford, CA 94305, USA.
⁷ Division of Veterinary Resources, Office of Research Services, NIH, Bethesda, MD 20892, USA.
⁸ School of Medicine, Stanford University, Stanford, CA 94305, USA; Drug Discovery Biology, Monash University, Melbourne, VIC 3800, Australia.
⁹ College of Life Sciences, University of Dundee, Dundee DD1 4HN, UK.
¹⁰ Leiden Institute of Chemistry and Institute of Chemical Immunology, Leiden University, 2311 EZ Leiden, the Netherlands.
¹¹ 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.
¹² Bio-Imaging Unit, Newcastle University, Newcastle upon Tyne NE2 4HH, UK. Electronic address: shoba.amarnath@newcastle.ac.uk.

Abstract

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.

Keywords: AEP; Foxp3; GvHD; LCMV; PD-1; PDL-1; colitis; iTreg; melanoma.

Publication types

Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Differentiation / immunology
Cells, Cultured
Colitis / immunology
Colitis / pathology
Cysteine Endopeptidases / metabolism*
Female
Forkhead Transcription Factors / metabolism*
Graft vs Host Disease / immunology
Graft vs Host Disease / pathology
Lymphocytic Choriomeningitis / immunology
Lymphocytic Choriomeningitis / pathology
Lymphocytic choriomeningitis virus / immunology
Melanoma, Experimental / immunology
Melanoma, Experimental / pathology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Programmed Cell Death 1 Receptor / metabolism*
T-Lymphocytes, Regulatory / cytology
T-Lymphocytes, Regulatory / immunology*
Th1 Cells / cytology
Th1 Cells / immunology*

Substances

Forkhead Transcription Factors
Foxp3 protein, mouse
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Cysteine Endopeptidases
asparaginyl endopeptidase, lysosomal

Abstract

Publication types

MeSH terms

Substances

Grant support