Abstract
CD4+CD25+ regulatory T cells (Treg) are potent immunosuppressive cells active in controlling normal pathological immune responses. The mechanisms of this suppression have been investigated under various conditions. In this report, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/death receptor 5 (DR5) was explored as one of the pivotal factors for the suppression and cytotoxicity induced by CD4+CD25+ Treg. Cell death was involved in the suppression induced by activated CD4+CD25+ Treg in vitro. The induction of CD4+ T cell death was not mediated by the CD95/CD95L pathway, but rather depended upon the upregulation of TRAIL in the Treg. Blocking the TRAIL/DR5 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro. Activated Treg displayed TRAIL-dependent cytotoxicity against CD4+ T cells in vivo. The prolonged survival of allogeneic skin grafts induced by Treg was inhibited by DR5-blocking antibodies. Our findings suggest that the TRAIL/DR5 pathway is one of the mechanisms used by Treg to regulate immune responses both in vitro and in vivo.
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Abbreviations
- 7-AAD:
-
7-amino actinomycin D
- acTregs:
-
activated CD4+CD25+Foxp3+ regulatory T cells
- CFSE:
-
carboxyfluorescein diacetate succinimidyl ester
- DR5:
-
death receptor 5
- MACS:
-
magnetic cell sorting
- MHC:
-
major histocompatibility complex
- OVA:
-
ovalbumin
- PBMCs:
-
peripheral blood monocytes
- PI:
-
propidium iodide
- TCR:
-
T-cell receptor
- Tg:
-
transgenic
- TNF:
-
tumor necrosis factor
- TRAIL:
-
TNF-related apoptosis inducing ligand
- WT:
-
wild type
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Acknowledgements
We appreciate Dr. Bin Sun for providing the gld and perforin deficient mice. We are grateful to Dr. Huabao Xiong and Yufang Shi for helpful comments. We thank Dr. Jianxin Gu for technical help. This work was supported by grants from the National Science Foundation of China (30571689, 30200259), Program of STCSM 055407032 and Program of NCET-04-0359 from the Ministry of Education of China to Ying Wang, and supplemented by 973 project 2007CB512401.
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Ren, X., Ye, F., Jiang, Z. et al. Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells. Cell Death Differ 14, 2076–2084 (2007). https://doi.org/10.1038/sj.cdd.4402220
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DOI: https://doi.org/10.1038/sj.cdd.4402220
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