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PD-1 inhibitory receptor downregulates asparaginyl endopeptidase and maintains Foxp3 transcription factor stability in induced regulatory T cells

Lookup NU author(s): Chaido Stathopoulou, Grace Mallett, Luke Liniany, Dr Rolando Berlinguer PalminiORCiD, Dr Arian Laurence, Professor Shoba AmarnathORCiD

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Abstract

CD4⁺T cell differentiation into multiple T helper cell (Th) 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_PDL1cells) and inducible regulatory T cells (iTregs). Tbet⁺iTreg_PDL1cells 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_PDL1cells and iTreg cells by specifically down regulating 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 (TIL) and during chronic viral infection. Collectively, this report has identified an intrinsic function for PD-1 in maintaining Foxp3 through proteolytic pathway

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Author(s): Stathopoulou C, Gangaplara A, Mallett G, Flomerfelt FA, Liniany LP, Knight D, Samsel LA, Berlinguer-Palmini R, Yim J, Felizardo TC, Eckhaus MA, Edgington-Mitchell L, Martinez-Fabregas J, Zhu J, Fowler DH, van Kasteren SI, Laurence A, Bogyo M, Watts C, Shevach EM, Amarnath S

Publication type: Article

Publication status: Published

Journal: Immunity

Year: 2018

Volume: 49

Issue: 2

Pages: 247-263.e7

Print publication date: 21/08/2018

Online publication date: 24/07/2018

Acceptance date: 17/05/2018

Date deposited: 27/06/2018

ISSN (print): 1074-7613

ISSN (electronic): 1097-4180

Publisher: Cell Press

URL: https://doi.org/10.1016/j.immuni.2018.05.006

DOI: 10.1016/j.immuni.2018.05.006

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