TLR9 engagement on CD4 T lymphocytes represses γ-radiation–induced apoptosis through activation of checkpoint kinase response elements
L Zheng, N Asprodites, AH Keene… - Blood, The Journal …, 2008 - ashpublications.org
L Zheng, N Asprodites, AH Keene, P Rodriguez, KD Brown, E Davila
Blood, The Journal of the American Society of Hematology, 2008•ashpublications.orgT 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 …
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 …
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 γ-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.
ashpublications.org