Cross-talk between the T cell antigen receptor and the glucocorticoid receptor regulates thymocyte development

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 (greater than or equal to 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.