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.
abstract: 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.
authors.affiliation: Immunology Division, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Brunner
authors.forename: Dietmar
authors.initials: D
authors.lastname: Herndler-Brandstetter
authors.forename: Christoph R
authors.initials: CR
authors.lastname: Arnold
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Wiegers
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Matthias
authors.initials: M
authors.lastname: Hackl
authors.forename: Johannes
authors.initials: J
authors.lastname: Grillari
authors.forename: María
authors.initials: M
authors.lastname: Moreno-Villanueva
authors.forename: Alexander
authors.initials: A
authors.lastname: Bürkle
authors.forename: Beatrix
authors.initials: B
authors.lastname: Grubeck-Loebenstein
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D004249:DNA Damage; D004260:DNA Repair; D005047:Etoposide / Q000494:pharmacology*; D006657:Histones / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000378:metabolism; D019169:Jurkat Cells; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018106:CD28 Antigens; C468783:H2AX protein, human; D006657:Histones; C569274:IL15 protein, human; D019409:Interleukin-15; C543845:MIRN24 microRNA, human; D035683:MicroRNAs; D012694:Serine; D005047:Etoposide