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. ShevachShoba Amarnath

Research output: Contribution to journalArticle

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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+iTregPDL1 cells) and inducible regulatory T (iTreg) cells. Tbet+iTregPDL1 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+iTregPDL1 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.

Original languageEnglish
Pages (from-to)247-263.e7
Number of pages25
JournalImmunity
Volume49
Issue number2
Early online date24 Jul 2018
DOIs
Publication statusPublished - 21 Aug 2018

Keywords

  • AEP
  • colitis
  • Foxp3
  • GvHD
  • iTreg
  • LCMV
  • melanoma
  • PD-1
  • PDL-1

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    Stathopoulou, C., Gangaplara, A., Mallett, G., Flomerfelt, F. A., Liniany, L. P., Knight, D., Samsel, L. A., Berlinguer-Palmini, R., Yim, J. J., Felizardo, T. C., Eckhaus, M. A., Edgington-Mitchell, L., Martinez-Fabregas, J., Zhu, J., Fowler, D. H., van Kasteren, S. I., Laurence, A., Bogyo, M., Watts, C., ... Amarnath, S. (2018). PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells. Immunity, 49(2), 247-263.e7. https://doi.org/10.1016/j.immuni.2018.05.006