Immunity
Volume 49, Issue 2, 21 August 2018, Pages 247-263.e7
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Article
PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells

https://doi.org/10.1016/j.immuni.2018.05.006Get rights and content
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Highlights

  • Asparaginyl endopeptidase (AEP) is expressed in induced regulatory T cells

  • AEP cleaves Foxp3 and Aep−/− mice have elevated numbers of peripheral Treg cells

  • AEP deficiency increases Treg cell frequency and numbers in GvHD and melanoma

  • PD-1 signaling maintains Foxp3 protein expression by inhibiting AEP

Summary

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.

Keywords

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

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These authors contributed equally

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