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A targeted glucocorticoid receptor antisense transgene increases thymocyte apoptosis and alters thymocyte development
L B King1, M S Vacchio, K Dixon
1Laboratory of Immune Cell Biology, National Cancer Institute, National Institutes of Health Bethesda, Maryland 20892, USA.
Abstract:
The exquisite sensitivity of thymocytes to steroid-induced apoptosis, the steroidogenic potential of thymic epithelial cells, and the ability of steroid synthesis inhibitors to enhance antigen-specific deletion of thymocytes in fetal thymic organ cultures suggest a role for glucocorticoids in thymocyte development. To address this further, transgenic mice that express antisense transcripts to the glucocorticoid receptor (GR) specifically in immature thymocytes were generated. The consequent hyporesponsiveness of thymocytes to glucocorticoids was accompanied by a reduction in thymic size, primarily owing to a decrease in the number of CD4+CD8+ cells. While an enhanced susceptibility to T cell receptor (TCR)-mediated apoptosis appeared to be partially responsible for this reduction, thymocyte loss could also be detected before thymocytes progressed to the CD4+CD8+ TCR alpha beta-expressing stage. These results suggest that glucocorticoids are necessary for survival and maturation of thymocytes, and are consistent with a role for steroids in both the transition from CD4-CD8- to CD4+CD8+ cells and the survival of CD4+CD8+ cells stimulated via the TCR.
Insights
Glucocorticoids are essential for thymocyte survival and maturation. Blocking the glucocorticoid receptor (GR) in mice reduced thymic size and impaired T cell development, highlighting steroids' critical role.
Area of Science:
- Immunology
- Endocrinology
- Developmental Biology
Background:
- Thymocytes exhibit sensitivity to steroid-induced apoptosis.
- Thymic epithelial cells possess steroidogenic potential.
- Steroid synthesis inhibitors impact thymocyte deletion in vitro.
Purpose of the Study:
- To investigate the role of glucocorticoids in thymocyte development.
- To determine the necessity of glucocorticoid receptor (GR) signaling for thymocyte survival and maturation.
Main Methods:
- Generation of transgenic mice with GR antisense transcripts in immature thymocytes.
- Assessment of thymic size and thymocyte populations (CD4+CD8+).
- Evaluation of thymocyte apoptosis susceptibility (TCR-mediated).
Main Results:
- Transgenic mice showed reduced thymic size and fewer CD4+CD8+ thymocytes.
- Thymocytes exhibited hyporesponsiveness to glucocorticoids.
- Increased susceptibility to T cell receptor (TCR)-mediated apoptosis was observed.
- Thymocyte loss occurred prior to CD4+CD8+ TCR alpha beta expression.
Conclusions:
- Glucocorticoids are crucial for thymocyte survival and maturation.
- Steroids play a role in the transition from CD4-CD8- to CD4+CD8+ stages.
- Glucocorticoids support the survival of mature CD4+CD8+ thymocytes upon TCR stimulation.