| First Author | Zheng L | Year | 2008 |
| Journal | Blood | Volume | 111 |
| Issue | 5 | Pages | 2704-13 |
| PubMed ID | 18086870 | Mgi Jnum | J:131583 |
| Mgi Id | MGI:3773986 | Doi | 10.1182/blood-2007-07-104141 |
| Citation | Zheng L, et al. (2008) TLR9 engagement on CD4 T lymphocytes represses {gamma}-radiation-induced apoptosis through activation of checkpoint kinase response elements. Blood 111(5):2704-13 |
| abstractText | 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 gamma-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. |
