DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation
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...
| Main Author: | |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/1721.1/124694 |
| _version_ | 1826214985763651584 |
|---|---|
| author | Sabatini, David M. |
| author2 | Whitehead Institute for Biomedical Research |
| author_facet | Whitehead Institute for Biomedical Research Sabatini, David M. |
| author_sort | Sabatini, David M. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:14:26Z |
| format | Article |
| id | mit-1721.1/124694 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:14:26Z |
| publishDate | 2020 |
| publisher | Wiley |
| record_format | dspace |
| spelling | mit-1721.1/1246942022-09-29T19:05:23Z DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation Sabatini, David M. Whitehead Institute for Biomedical Research Massachusetts Institute of Technology. Department of Biology Immunology and Allergy Pharmacology (medical) Transplantation 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. National Institutes of Health (U.S.) (Grant R21AI114223) National Institutes of Health (U.S.) (Grant R01AI136503) 2020-04-16T14:56:39Z 2020-04-16T14:56:39Z 2018-08-17 2020-01-30T14:22:27Z Article http://purl.org/eprint/type/JournalArticle 1600-6135 1600-6143 https://hdl.handle.net/1721.1/124694 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) en 10.1111/ajt.14995 American journal of transplantation Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Wiley PMC |
| spellingShingle | Immunology and Allergy Pharmacology (medical) Transplantation Sabatini, David M. DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title | DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title_full | DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title_fullStr | DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title_full_unstemmed | DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title_short | DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation |
| title_sort | deptor modulates activation responses in cd4 t cells and enhances immunoregulation following transplantation |
| topic | Immunology and Allergy Pharmacology (medical) Transplantation |
| url | https://hdl.handle.net/1721.1/124694 |
| work_keys_str_mv | AT sabatinidavidm deptormodulatesactivationresponsesincd4tcellsandenhancesimmunoregulationfollowingtransplantation |