Increased p300 Expression Inhibits Glucocorticoid Receptor-T-Cell Receptor Antagonism but Does Not Affect Thymocyte Positive Selection

Abstract

Positive selection of T cells is postulated to be dependent on the counterinteraction between glucocorticoid receptor (GR)- and T-cell-receptor (TCR)-induced death signals. In this study we used T-cell-specific expression of p300 to investigate whether GR-TCR cross talk between thymocytes was affected. Activation of the p300-transgenic T cells led to enhanced thymocyte proliferation and increased interleukin 2 production. Thymocyte death, induced by TCR engagement, was no longer prevented by dexamethasone in p300-transgenic mice, indicating an absence of GR-TCR cross-inhibition. This was accompanied by a 50% reduction in the number of thymocytes in p300-transgenic mice. However, the CD4/CD8 profile of thymocytes remained unchanged in p300-transgenic mice. There was no effect on positive selection of the bulk thymocytes or thymocytes with transgenic TCR in p300-transgenic mice. In addition, there was no apparent TCR repertoire “hole” in the selected antigens examined. Our results illustrate a critical role of CBP/p300 in thymic GR-TCR counterinteraction yet do not support the involvement of GR-TCR antagonism in thymocyte positive selection.

This project was supported by grant NSC 89-2311-B001-005 from the National Science Council and a grant from Academia Sinica, Taipei, Taiwan, Republic of China.

We thank Richard Goodman, Roger Perlmutter, Dimitris Kioussis, John Kung, and Chung Wang for providing the plasmids and reagents. We thank Bruce Boothby for helpful discussions and Ken Deen for editing the manuscript.