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International Immunology Advance Access originally published online on August 28, 2006
International Immunology 2006 18(10):1405-1411; doi:10.1093/intimm/dxl082
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© The Japanese Society for Immunology. 2006. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

TAK1 is indispensable for development of T cells and prevention of colitis by the generation of regulatory T cells

Shintaro Sato1, Hideki Sanjo2, Tohru Tsujimura3, Jun Ninomiya-Tsuji4, Masahiro Yamamoto2, Taro Kawai1, Osamu Takeuchi1,2 and Shizuo Akira1,2

1 Akira Innate Immunity Project, Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
2 Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan
3 Department of Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan
4 Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, NC 27695-7633, USA

Correspondence to: S. Akira; E-mail: sakira{at}biken.osaka-u.ac.jp

Transforming growth factor (TGF)-ß-activating kinase 1 (TAK1) is critical for Toll-like receptor- and tumor necrosis factor-mediated cellular responses. In B cells, TAK1 is essential for the activation of mitogen-activated protein kinases (MAPKs), but not nuclear factor-{kappa}B (NF-{kappa}B), in antigen receptor signaling. In this study, we generate T cell-specific TAK1-deficient (LckCre/+Tak1flox/flox) mice and show that TAK1 is indispensable for the maintenance of peripheral CD4 and CD8 T cells. In thymocytes, TAK1 is essential for TCR-mediated activation of both NF-{kappa}B and MAPKs. Additionally, LckCre/+Tak1flox/flox mice developed colitis as they aged. In these mice, accumulations of activated/memory T cells as well as B cells were observed. Development of regulatory T (Treg) cells in thymus was abrogated in LckCre/+Tak1flox/flox mice, suggesting that the loss of Treg cells is the cause of the disease. Together, the results show that TAK1, by controlling the generation of central Treg cells, is important for preventing spontaneously developing colitis.

Keywords: IBD, regulatory T cells, signal transduction, TCR

Transmitting editor: K. Takatsu


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