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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.
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IMMUNOBIOLOGY
TLR9 engagement on CD4 T lymphocytes represses  -radiation–induced apoptosis through activation of checkpoint kinase response elements
Liqin Zheng1,
Nicole Asprodites1,
Angela H. Keene1,
Paulo Rodriguez2,
Kevin D. Brown3, and
Eduardo Davila1,2
1 Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans;
2 Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans; and
3 Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville
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 after 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 cells displayed higher radio resistance than TLR9-stimulated MyD88–/– T cells and responded to antigenic stimulation after 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 checkpoint activity, potentially allowing for combinatorial immunotherapy and radiotherapy.
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