TLR9 engagement on CD4 T lymphocytes represses gamma-radiation-induced apoptosis through activation of checkpoint kinase response elements.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Zheng L,Asprodites N,Keene AH,Rodriguez P,Brown KD,Davila E

doi

10.1182/blood-2007-07-104141

subject

Has Abstract

pub_date

2008-03-01 00:00:00

pages

2704-13

issue

5

eissn

0006-4971

issn

1528-0020

pii

blood-2007-07-104141

journal_volume

111

pub_type

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