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Increased p300 expression inhibits glucocorticoid receptor-T-cell receptor antagonism but does not affect thymocyte
Cheng-Tai Yu1, Ming-Hsien Lin Feng, Hsiu-ming Shih
1Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, Taiwan, Republic of China.
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.
Insights
Glucocorticoid receptor (GR) and T-cell receptor (TCR) interactions are crucial for T cell selection. This study shows CBP/p300 plays a key role in GR-TCR cross-inhibition but not in thymocyte positive selection.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- T cell selection in the thymus involves complex signaling pathways.
- Glucocorticoid receptor (GR) and T-cell receptor (TCR) signaling pathways are known to interact.
- The role of CBP/p300 in this GR-TCR cross-talk and its impact on T cell selection is not fully understood.
Purpose of the Study:
- To investigate the role of CBP/p300 in the cross-talk between GR and TCR signaling during thymocyte development.
- To determine if CBP/p300 influences thymocyte proliferation, death, and positive selection.
- To elucidate the mechanism of GR-TCR counteraction in thymocytes.
Main Methods:
- Utilized T-cell-specific expression of p300 in transgenic mice.
- Analyzed thymocyte proliferation, death, and interleukin 2 production upon activation.
- Examined the effect of dexamethasone on TCR-induced thymocyte death.
- Assessed CD4/CD8 profiles and TCR repertoire in transgenic mice.
Main Results:
- T-cell-specific p300 expression enhanced thymocyte proliferation and IL-2 production.
- Dexamethasone failed to prevent TCR-induced thymocyte death in p300-transgenic mice, indicating loss of GR-TCR cross-inhibition.
- A 50% reduction in thymocyte numbers was observed in p300-transgenic mice, without altering the CD4/CD8 profile.
- Positive selection of thymocytes and TCR repertoire remained unaffected.
Conclusions:
- CBP/p300 is critical for thymic GR-TCR counterinteraction.
- GR-TCR antagonism is not essential for thymocyte positive selection.
- The study highlights a novel role for CBP/p300 in regulating T cell development signaling pathways.