Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death

The life-long homeostasis of memory CD8+ T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8+CD28− T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regul...

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Main Authors:	Brunner, Stefan, Herndler-Brandstetter, Dietmar, Arnold, Christoph R, Wiegers, Gerrit Jan, Villunger, Andreas, Hackl, Matthias, Grillari, Johannes, Moreno-Villanueva, María, Bürkle, Alexander, Grubeck-Loebenstein, Beatrix
Format:	Online
Language:	English
Published:	Blackwell Publishing Ltd 2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427896/

id	pubmed-3427896
recordtype	oai_dc
spelling	pubmed-34278962012-08-27 Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death Brunner, Stefan Herndler-Brandstetter, Dietmar Arnold, Christoph R Wiegers, Gerrit Jan Villunger, Andreas Hackl, Matthias Grillari, Johannes Moreno-Villanueva, María Bürkle, Alexander Grubeck-Loebenstein, Beatrix Original Articles The life-long homeostasis of memory CD8+ T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8+CD28− T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8+CD28− T cells have not yet been elucidated. In this study, we demonstrate that the miR-23∼24∼27 cluster is up-regulated during post-thymic CD8+ T-cell differentiation in humans. The increased expression of miR-24 in CD8+CD28− T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8+CD28− when compared to CD8+CD28+ T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8+CD28− T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8+CD28− T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8+CD28− T cells in humans. Blackwell Publishing Ltd 2012-08 /pmc/articles/PMC3427896/ /pubmed/22435726 http://dx.doi.org/10.1111/j.1474-9726.2012.00819.x Text en © 2012 The Authors. Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Brunner, Stefan Herndler-Brandstetter, Dietmar Arnold, Christoph R Wiegers, Gerrit Jan Villunger, Andreas Hackl, Matthias Grillari, Johannes Moreno-Villanueva, María Bürkle, Alexander Grubeck-Loebenstein, Beatrix
spellingShingle	Brunner, Stefan Herndler-Brandstetter, Dietmar Arnold, Christoph R Wiegers, Gerrit Jan Villunger, Andreas Hackl, Matthias Grillari, Johannes Moreno-Villanueva, María Bürkle, Alexander Grubeck-Loebenstein, Beatrix Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
author_facet	Brunner, Stefan Herndler-Brandstetter, Dietmar Arnold, Christoph R Wiegers, Gerrit Jan Villunger, Andreas Hackl, Matthias Grillari, Johannes Moreno-Villanueva, María Bürkle, Alexander Grubeck-Loebenstein, Beatrix
author_sort	Brunner, Stefan
title	Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
title_short	Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
title_full	Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
title_fullStr	Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
title_full_unstemmed	Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death
title_sort	upregulation of mir-24 is associated with a decreased dna damage response upon etoposide treatment in highly differentiated cd8+ t cells sensitizing them to apoptotic cell death
description	The life-long homeostasis of memory CD8+ T cells as well as persistent viral infections have been shown to facilitate the accumulation of highly differentiated CD8+CD28− T cells, a phenomenon that has been associated with an impaired immune function in humans. However, the molecular mechanisms regulating homeostasis of CD8+CD28− T cells have not yet been elucidated. In this study, we demonstrate that the miR-23∼24∼27 cluster is up-regulated during post-thymic CD8+ T-cell differentiation in humans. The increased expression of miR-24 in CD8+CD28− T cells is associated with decreased expression of the histone variant H2AX, a protein that plays a key role in the DNA damage response (DDR). Following treatment with the classic chemotherapeutic agent etoposide, a topoisomerase II inhibitor, apoptosis was increased in CD8+CD28− when compared to CD8+CD28+ T cells and correlated with an impaired DDR in this cell type. The reduced capacity of CD8+CD28− T cell to repair DNA was characterized by the automated fluorimetric analysis of DNA unwinding (FADU) assay as well as by decreased phosphorylation of H2AX at Ser139, of ATM at Ser1981, and of p53 at Ser15. Interleukin (IL)-15 could prevent etoposide-mediated apoptosis of CD8+CD28− T cells, suggesting a role for IL-15 in the survival and the age-dependent accumulation of CD8+CD28− T cells in humans.
publisher	Blackwell Publishing Ltd
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3427896/
_version_	1611552276219953152

Upregulation of miR-24 is associated with a decreased DNA damage response upon etoposide treatment in highly differentiated CD8+ T cells sensitizing them to apoptotic cell death

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