Scientific Publications by FDA Staff
Stem Cells 1996 Sep;14(5):490-500
Cross-talk between the T cell antigen receptor and the glucocorticoid receptor regulates thymocyte development.
Ashwell JD, King LB, Vacchio MS
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.
|Category: Journal Article, Review|
|PubMed ID: #8888490||DOI: 10.1002/stem.140490|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2012-12-25|