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A developmental switch from TCR delta enhancer to TCR alpha enhancer function during thymocyte maturation
C Hernández-Munain1, B P Sleckman, M S Krangel
1Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Immunity
|July 14, 1999
Summary
T-cell receptor (TCR) alpha/delta locus regulation involves stage-specific enhancers. Edelta is active in early thymocytes, while Ealpha activates later, with TCR delta downregulation linked to Edelta inactivation and chromosomal excision.
Area of Science:
- Immunology
- Molecular Biology
- Developmental Biology
Background:
- V(D)J recombination and transcription at the TCR alpha/delta locus are crucial for T-cell development.
- Three cis-acting elements, TCR delta enhancer (Edelta), TCR alpha enhancer (Ealpha), and T early alpha (TEA) promoter, regulate this locus.
Purpose of the Study:
- To investigate the in vivo occupancy and function of Edelta, Ealpha, and TEA during thymocyte development.
- To elucidate the mechanisms regulating TCR delta downregulation in developing T-cells.
Main Methods:
- Analysis of enhancer and promoter occupancy in developing thymocytes.
- Functional studies of cis-acting elements during T-cell development.
Main Results:
- Edelta and Ealpha exhibit developmental-stage-specific enhancer activity.
- Edelta is active in double-negative III thymocytes, while Ealpha is active in double-positive thymocytes.
- Ealpha and TEA are occupied early, prior to activation, and Edelta downregulation correlates with loss of occupancy.
Conclusions:
- TCR delta downregulation in double-positive thymocytes is a two-step process involving Edelta inactivation and chromosomal excision.
- Developmental stage-specific regulation of enhancers controls TCR alpha/delta locus activity.