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PNAS 97 (13): 7319-7324

Copyright © 2000 by the National Academy of Sciences.

Cell Biology
 Crosstalk pathway for inhibition of glucocorticoid-induced apoptosis by T cell receptor signaling

Christina A. M. Jamieson and Keith R. Yamamoto*

Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94143-0450

Contributed by Keith R. Yamamoto, May 1, 2000

Activation of the glucocorticoid receptor (GR) triggers apoptosis in T cells. However, activation of the T cell antigen receptor (TCR) blocks glucocorticoid-induced apoptosis, implying functional crosstalk between these two distinct signaling systems. By reconstructing or selectively blocking TCR-stimulated signaling pathways, we show here that TCR activation of the mitogen-activated protein kinase kinase/extracellular signal regulated kinase (MEK/ERK) cascade via Ras is necessary and sufficient to inhibit GR-mediated death in immortalized T and thymocyte cell lines and in primary T cells. Moreover, we found that activation of various pathway components (TCR, Ras, MEK1) altered the transcriptional regulatory activity of GR. In contrast, phosphatidylinositol 3-kinase and Akt, which down-regulate other lymphocyte apoptosis pathways, did not inhibit glucocorticoid-induced apoptosis. Our findings, which link signaling from the TCR cell surface receptor to that from the GR intracellular receptor, demonstrate the importance of the integration of signal transduction pathways in defining regulatory circuits. Because the TCR/Ras/MEK pathway has been shown previously to be essential for positive selection of thymocytes, the TCR/Ras/MEK signaling to GR crosstalk described herein may affect T cell development and homeostasis.

* To whom reprint requests should be addressed. E-mail: yamamoto{at}cgl.ucsf.edu.

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