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

TY - JOUR

T1 - PD-1 Inhibitory Receptor Downregulates Asparaginyl Endopeptidase and Maintains Foxp3 Transcription Factor Stability in Induced Regulatory T Cells

AU - Stathopoulou, Chaido

AU - Gangaplara, Arunakumar

AU - Mallett, Grace

AU - Flomerfelt, Francis A.

AU - Liniany, Lukasz P.

AU - Knight, David

AU - Samsel, Leigh A.

AU - Berlinguer-Palmini, Rolando

AU - Yim, Joshua J.

AU - Felizardo, Tania C.

AU - Eckhaus, Michael A.

AU - Edgington-Mitchell, Laura

AU - Martinez-Fabregas, Jonathan

AU - Zhu, Jinfang

AU - Fowler, Daniel H.

AU - van Kasteren, Sander I.

AU - Laurence, Arian

AU - Bogyo, Matthew

AU - Watts, Colin

AU - Shevach, Ethan M.

AU - Amarnath, Shoba

PY - 2018/8/21

Y1 - 2018/8/21

N2 - 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.

AB - 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.

KW - AEP

KW - colitis

KW - Foxp3

KW - GvHD

KW - iTreg

KW - LCMV

KW - melanoma

KW - PD-1

KW - PDL-1

UR - https://www.scopus.com/pages/publications/85049506077

U2 - 10.1016/j.immuni.2018.05.006

DO - 10.1016/j.immuni.2018.05.006

M3 - Article

C2 - 30054205

AN - SCOPUS:85049506077

SN - 1074-7613

VL - 49

SP - 247-263.e7

JO - Immunity

JF - Immunity

IS - 2

ER -