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Science 26 August 2005:
Vol. 309. no. 5739, pp. 1380 - 1384
DOI: 10.1126/science.1113401
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Reports

Toll-Like Receptor 8-Mediated Reversal of CD4+ Regulatory T Cell Function

Guangyong Peng, Zhong Guo, Yukiko Kiniwa, Kui shin Voo, Weiyi Peng, Tihui Fu, Daniel Y. Wang, Yanchun Li, Helen Y. Wang, Rong-Fu Wang*

CD4+ regulatory T (Treg) cells have a profound ability to suppress host immune responses, yet little is understood about how these cells are regulated. We describe a mechanism linking Toll-like receptor (TLR) 8 signaling to the control of Treg cell function, in which synthetic and natural ligands for human TLR8 can reverse Treg cell function. This effect was independent of dendritic cells but required functional TLR8-MyD88-IRAK4 signaling in Treg cells. Adoptive transfer of TLR8 ligand-stimulated Treg cells into tumor-bearing mice enhanced anti-tumor immunity. These results suggest that TLR8 signaling could play a critical role in controlling immune responses to cancer and other diseases.

The Center for Cell and Gene Therapy and Department of Immunology, Baylor College of Medicine, Houston, TX 77030, USA.

* To whom correspondence should be addressed. E-mail: Rongfuw{at}bcm.tmc.edu

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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R. M. Prins, D. D. Vo, H. Khan-Farooqi, M.-Y. Yang, H. Soto, J. S. Economou, L. M. Liau, and A. Ribas (2006)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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