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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2704-2713. Prepublished online as a Blood First Edition Paper on December 17, 2007; DOI 10.1182/blood-2007-07-104141. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-07-104141v1 111/5/2704    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Zheng, L. Articles by Davila, E. Search for Related Content PubMed PubMed Citation Articles by Zheng, L. Articles by Davila, E. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 30, 2007 Accepted December 6, 2007 TLR9 engagement on CD4 T lymphocytes represses -radiation-induced apoptosis through activation of checkpoint kinase response elements Liqin Zheng, Nicole Asprodites, Angela H Keene, Paulo Rodriguez, Kevin D Brown, and Eduardo Davila* Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, United States Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, LA, United States Department of Biochemistry and Molecular Biology, University of Florida, College of Medicine, Gainesville, FL, United States * Corresponding author; email: edavil{at}lsuhsc.edu. T-cell based therapies have much promise in cancer treatment. This approach may be enhanced if used in combination with radiotherapy provided that tumor-specific T-cells can be protected against the effects of radiotherapy. Previously, we demonstrated that administration of TLR9 ligand into mice decreased activation- and serum-deprivation-induced cell death in T-cells. We hypothesized that TLR9 engagement on T-lymphocytes decreased apoptosis following cellular stress. We show that TLR9 engagement on murine CD4 T-cells reduces -radiation-induced apoptosis as judged by decreased Annexin-V/PI staining, caspase-3-activation and PARP-cleavage. TLR9-stimulated cells show heightened accumulation at the G2 cell cycle phase and increased DNA repair rates. Irradiated, TLR9-engaged cells showed higher levels of phosphorylated Chk1 and Chk2. While the levels of activated ATM in response to IR did not differ between TLR9-stimulated and unstimulated cells, inhibition of ATM/ATR and Chk1/Chk2 kinases abolished the radioprotective effects in TLR9-stimulated cells. In vivo, TLR9-stimulated T-cells displayed higher radioresistance than TLR9-stimulated MyD88-/- T-cells and responded to antigenic stimulation following total body irradiation. These findings show, for the first time, that TLR9 engagement on CD4 T-cells reduces IR-induced apoptosis by influencing cell cycle check point activity, potentially allowing for combinatorial immunotherapy and radiotherapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: N. Asprodites, L. Zheng, D. Geng, C. Velasco-Gonzalez, L. Sanchez-Perez, and E. Davila Engagement of Toll-like receptor-2 on cytotoxic T-lymphocytes occurs in vivo and augments antitumor activity FASEB J, October 1, 2008; 22(10): 3628 - 3637. [Abstract] [Full Text] [PDF]

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