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124694 |
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|a dc
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|a Sabatini, David M.
|e author
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|a Whitehead Institute for Biomedical Research
|e contributor
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|a Massachusetts Institute of Technology. Department of Biology
|e contributor
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|a DEPTOR modulates activation responses in CD4+ T cells and enhances immunoregulation following transplantation
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|b Wiley,
|c 2020-04-16T14:56:39Z.
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|z Get fulltext
|u https://hdl.handle.net/1721.1/124694
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|a 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.
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|a National Institutes of Health (U.S.) (Grant R21AI114223)
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|a National Institutes of Health (U.S.) (Grant R01AI136503)
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|a en
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|a Immunology and Allergy
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|a Pharmacology (medical)
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|a Transplantation
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|a Article
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|t 10.1111/ajt.14995
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|t American journal of transplantation
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