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Am J Transplant. 2019 Jan;19(1):77-88. doi: 10.1111/ajt.14995. Epub 2018 Aug 17.

DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation.

Wedel J1,2,3, Bruneau S1,2,3, Liu K1,2,3, Kong SW3,4, Sage PT5,6, Sabatini DM7,8,9, Laplante M10, Briscoe DM1,2,3.

Author information

1
Transplant Research Program, Boston Children's Hospital, Boston, MA, USA.
2
Division of Nephrology, Department of Medicine, Boston Children's Hospital, Boston, MA, USA.
3
Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
4
Computational Health Informatics Program, Boston Children's Hospital, Boston, MA, USA.
5
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA.
6
Evergrande Center for Immunologic Diseases, Harvard Medical School, Boston, MA, USA.
7
Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
8
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
9
Howard Hughes Medical Institute, Cambridge, MA, USA.
10
Centre de recherche de l'Institut Universitaire de Cardiologie et de Pulmonologie de Quebec, Faculté de médecine, Université Laval, Quebec, QC, Canada.

Abstract

DEPTOR is an evolutionarily conserved cell-intrinsic binding partner of mTOR that functions as a negative regulator of signaling responses. In this study, we show that DEPTOR is expressed within CD4+ T cells, and we observed that its relative level of expression modulates differentiation as well as glucose utilization within CD4+ T effectors in vitro. Using knock-in mice, we also find that induced expression of DEPTOR within CD4+ T regulatory cells stabilizes Foxp3 expression, shifts metabolism toward oxidative phosphorylation, and increases survival and suppressive function. In vivo, fully MHC mismatched cardiac allograft survival is significantly prolonged in knock-in recipients and sustained recipient expression of DEPTOR in combination with costimulatory blockade induces long-term graft survival. Furthermore, we show that the induced expression of DEPTOR in CD4+ T effectors fails to inhibit acute allograft rejection. Rather, prolonged survival is dominantly mediated via induced expression and function of DEPTOR within recipient CD4+ T regulatory cells. These collective findings identify DEPTOR as a novel protein that functions in CD4+ T cells to augment immunoregulation in vitro and in vivo.

KEYWORDS:

T cell biology; basic (laboratory) research / science; immune regulation; immunobiology; immunosuppression/immune modulation; lymphocyte biology; rejection; tolerance

PMID:
29969188
PMCID:
PMC6310634
[Available on 2020-01-01]
DOI:
10.1111/ajt.14995

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