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Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition

Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Tre...

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Autores principales: Liu, Xia, Mo, Wei, Ye, Jian, Li, Lingyun, Zhang, Yanping, Hsueh, Eddy C., Hoft, Daniel F., Peng, Guangyong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770447/
https://www.ncbi.nlm.nih.gov/pubmed/29339767
http://dx.doi.org/10.1038/s41467-017-02689-5
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author Liu, Xia
Mo, Wei
Ye, Jian
Li, Lingyun
Zhang, Yanping
Hsueh, Eddy C.
Hoft, Daniel F.
Peng, Guangyong
author_facet Liu, Xia
Mo, Wei
Ye, Jian
Li, Lingyun
Zhang, Yanping
Hsueh, Eddy C.
Hoft, Daniel F.
Peng, Guangyong
author_sort Liu, Xia
collection PubMed
description Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence. Human Treg-induced T-cell senescence can be prevented via inhibition of the DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify molecular mechanisms of human Treg cell suppression and indicate that targeting Treg-induced T-cell senescence is a checkpoint for immunotherapy against cancer and other diseases associated with Treg cells.
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spelling pubmed-57704472018-01-22 Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition Liu, Xia Mo, Wei Ye, Jian Li, Lingyun Zhang, Yanping Hsueh, Eddy C. Hoft, Daniel F. Peng, Guangyong Nat Commun Article Defining the suppressive mechanisms used by regulatory T (Treg) cells is critical for the development of effective strategies for treating tumors and chronic infections. The molecular processes that occur in responder T cells that are suppressed by Treg cells are unclear. Here we show that human Treg cells initiate DNA damage in effector T cells caused by metabolic competition during cross-talk, resulting in senescence and functional changes that are molecularly distinct from anergy and exhaustion. ERK1/2 and p38 signaling cooperate with STAT1 and STAT3 to control Treg-induced effector T-cell senescence. Human Treg-induced T-cell senescence can be prevented via inhibition of the DNA damage response and/or STAT signaling in T-cell adoptive transfer mouse models. These studies identify molecular mechanisms of human Treg cell suppression and indicate that targeting Treg-induced T-cell senescence is a checkpoint for immunotherapy against cancer and other diseases associated with Treg cells. Nature Publishing Group UK 2018-01-16 /pmc/articles/PMC5770447/ /pubmed/29339767 http://dx.doi.org/10.1038/s41467-017-02689-5 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Liu, Xia
Mo, Wei
Ye, Jian
Li, Lingyun
Zhang, Yanping
Hsueh, Eddy C.
Hoft, Daniel F.
Peng, Guangyong
Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title_full Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title_fullStr Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title_full_unstemmed Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title_short Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition
title_sort regulatory t cells trigger effector t cell dna damage and senescence caused by metabolic competition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5770447/
https://www.ncbi.nlm.nih.gov/pubmed/29339767
http://dx.doi.org/10.1038/s41467-017-02689-5
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