Cross‐Talk between the T Cell Antigen Receptor and the Glucocorticoid Receptor Regulates Thymocyte Development

Abstract

The fate of an immature thymocyte, life or death, is largely determined by the ligand-specificity of its T cell antigen receptor (TCR). The default pathway for thymocytes bearing TCRs with subthreshold avidity for self-antigens is death (death by neglect). Thymocytes bearing TCRs with high avidity for self also undergo apoptosis (negative selection). Those thymocytes with intermediate avidities, or that perhaps recognize self-peptides that have partial agonist or antagonist properties, survive and differentiate into mature immunocompetent T cells (positive selection). How TCR avidity is interpreted as a "rescue" signal or a death signal is unknown. Based upon a T cell hybridoma model, our laboratory proposed that glucocorticoids, which themselves are potent inducers of thymocyte apoptosis, antagonize TCR-mediated thymocyte deletion and allow positive selection to occur. In fact, epithelial cells in the thymus proved to be a source of steroid production, and interference with steroid synthesis in fetal thymic organ culture resulted in a greatly enhanced sensitivity of thymocytes to TCR-mediated apoptosis. Transgenic mice with reduced glucocorticoid receptor (GR) levels were produced by tissue-specific expression of GR antisense. Thymocytes in these mice had high levels of spontaneous apoptosis, and were exquisitely sensitive to deletion induced by cross-linking the TCR. Moreover, there was a very large (> or = 90%) loss of CD4+CD8+ thymocytes, signifying a block at the CD4-CD8- to CD4+CD8+ transition, perhaps due to apoptosis of cells upon engagement of the pre-TCR in the absence of an antagonizing glucocorticoid stimulus. The molecular mechanism of the antagonism is currently being investigated. These data indicate that there is cross-talk in thymocytes between the TCR and glucocorticoid signaling pathways resulting in apoptosis, and that locally produced steroids, in a paracrine fashion, participate in setting the TCR avidity thresholds that determine whether developing thymocytes survive or die, and therefore help to mold the antigen-specific T cell repertoire.