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A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection
B J Calnan1, S Szychowski, F K Chan
1Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.
Abstract:
The transcription factor Nur77, an orphan member of the nuclear hormone receptor superfamily, is highly expressed during T cell receptor-signaled apoptosis, suggesting a possible role for Nur77 in negative selection. We examined this by generating two sets of transgenic mice. In one set of mice, a dominant-negative Nur77 mutant is constitutively expressed and the other in which wild-type Nur77 protein is constitutively expressed in developing thymocytes. We report that inhibition of endogenous Nur77 by the dominant-negative mutant perturbed T cell development and inhibited antigen-induced negative selection in F5T cell receptor transgenic mice. Constitutive expression of wild-type Nur77 protein induced apoptosis in developing thymocytes, resulting in a decreased number of thymocytes and mature T cells. Together, these data support a role for Nur77 in the downstream signaling events in antigen-induced negative selection.
Insights
The transcription factor Nur77 plays a key role in T cell development and negative selection. Its inhibition disrupts T cell maturation, while its overexpression induces thymocyte apoptosis, confirming its function in T cell receptor signaling.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Nur77 (nuclear orphan receptor 77) is a transcription factor highly expressed during T cell receptor (TCR)-induced apoptosis.
- Its expression pattern suggests a potential role in T cell negative selection, a critical process for immune tolerance.
Purpose of the Study:
- To investigate the role of Nur77 in T cell development and negative selection.
- To elucidate the downstream signaling events mediated by Nur77 in response to TCR signaling.
Main Methods:
- Generation of transgenic mice expressing either a dominant-negative Nur77 mutant or wild-type Nur77 in developing thymocytes.
- Analysis of T cell development and negative selection in these genetically modified mouse models, including F5TCR transgenic mice.
Main Results:
- Inhibition of endogenous Nur77 using a dominant-negative mutant impaired T cell development and blocked antigen-induced negative selection.
- Constitutive expression of wild-type Nur77 led to increased apoptosis in developing thymocytes, reducing thymocyte and mature T cell numbers.
Conclusions:
- Nur77 is essential for proper T cell development and the process of negative selection.
- These findings establish Nur77 as a critical component in the downstream signaling pathways governing T cell tolerance induction.