Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38α Activation

Abstract

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-1^a express a scaffolding protein, transforming growth factor β-activated protein kinase 1-binding protein 1 (TAB1), that negatively regulates TCR signaling through the activation of mitogen-activated protein kinase p38α. 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 p38α, 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 p38α in anergic T cells regulates the maintenance of T-cell unresponsiveness both by inhibiting IL-2 production and by promoting IL-10 production.

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Regulation of the Maintenance of Peripheral T-Cell Anergy by TAB1-Mediated p38α Activation

We thank Mark I. Greene, Makoto Katsumata, and Isao Sano for help; Masakatsu Ueda for technical assistance; and Dalibor Breznan for editorial assistance with the manuscript. We are also grateful to Kunihiro Matsumoto, Roger Davis, and Stephen T. Smale for plasmids; SmithKline Beecham for SB203580; and Hajome Karasuyama for a cytokine-producing cell line.

This study was supported by grants-in-aid from the Ministry of Education, Science, Sports, and Culture in Japan and by the Nagasaki Medical Association.