DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation
Name
nihms-979297.pdf
Description
Accepted version
Size
1.04 MB
Format
Adobe PDF
Checksum (MD5)
41f9869a9dcab052aadbb8584ed8bbcf
Author(s)
Sabatini, David M.
Date Issued
August 17, 2018
Journal
American journal of transplantation
Publisher
Wiley
Citation
Wedel, Johannes et al. "DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation." American journal of transplantation 19 (2018): 77-88 © 2018 The Author(s)
Version
Author's final manuscript
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.
Subjects
Immunology and Allergy
Pharmacology (medical)
Transplantation
MIT Department
Whitehead Institute for Biomedical Research
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1111/ajt.14995
