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Molecular and Cellular Biology, August 2004, p. 6957-6966, Vol. 24, No. 16
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.16.6957-6966.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38{alpha} Activation

Kozo Ohkusu-Tsukada,1 Norio Tominaga,1,2 Heiichiro Udono,1,3 and Katsuyuki Yui1*

Division of Immunology, Department of Translational Medical Sciences,1 Division of Medical Virology, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523,2 Laboratory for Immunochaperones, RIKEN Research Center for Allergy and Immunology, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan3

Received 15 January 2004/ Returned for modification 24 February 2004/ Accepted 18 May 2004

In anergic T cells, T-cell receptor (TCR)-mediated responses are functionally inactivated by negative regulatory signals whose mechanisms are poorly understood. Here, we show that CD4+ T cells anergized in vivo by superantigen Mls-1a express a scaffolding protein, transforming growth factor ß-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38{alpha}. TAB1 was not expressed in naive and activated CD4+ T cells. Inhibition of p38 activity in anergic T cells by a chemical inhibitor resulted in the recovery of interleukin 2 (IL-2) and the inhibition of IL-10 secretion. T-cell hybridoma 2B4 cells transduced with TAB1-containing retrovirus (TAB1-2B4 cells) showed activated p38{alpha}, inhibited extracellular signal-regulated kinase (ERK) activity, culminating in reduced IL-2 levels and increased IL-10 production. The use of a p38 inhibitor or cotransfection of a dominant-negative form of p38 in TAB1-2B4 cells resulted in the recovery of ERK activity and IL-2 production. These results imply that TAB1-mediated activation of p38{alpha} in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.

* Corresponding author. Mailing address: Division of Immunology, Department of Translational Medical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. Phone: 81-95-849-7070. Fax: 81-95-849-7073. E-mail: katsu{at}net.nagasaki-u.ac.jp.

Molecular and Cellular Biology, August 2004, p. 6957-6966, Vol. 24, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.16.6957-6966.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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