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A role for accessibility to self-peptide-self-MHC complexes in intrathymic negative selection.
C Viret1, D B Sant'Angelo, X He
1Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|March 20, 2001
Summary
Negative selection of T cells occurs in the thymus, influenced by self-peptide-MHC accessibility. This process impacts T cell receptor (TCR) development regardless of anatomical site.
Area of Science:
- Immunology
- Cell Biology
- Developmental Biology
Background:
- The anatomical sites of intrathymic T cell selection are debated.
- Understanding T cell selection is crucial for autoimmune disease research.
Purpose of the Study:
- To investigate in vivo T cell negative selection by self-peptide-MHC complexes with differential tissue expression.
- To determine if anatomical location influences T cell negative selection.
Main Methods:
- Utilized Y-Ae mAb and 1H3.1 TCR specific for E alpha 52-68 peptide bound to I-A(b).
- Generated 1H3.1 TCR-transgenic mice bred to mice with I-E alpha transgenes under various tissue-specific promoters.
- Analyzed thymic cellularity, T cell populations (V beta 6(+)CD4(+) cells), and in vitro responses.
Main Results:
- All double-transgenic mice showed diminished thymic cellularity and depletion of V beta 6(+)CD4(+) lymph node cells.
- CD4(+)CD8(+) thymocyte numbers were significantly reduced, indicating effective in vivo negative selection in the thymic cortex.
- Both cortical epithelial cells and dendritic cells supported negative selection, though with differing efficiencies.
Conclusions:
- Negative selection of autoreactive T cells can occur effectively in the thymic cortex in vivo.
- Accessibility to self-peptide-MHC complexes, not just anatomical site, determines negative selection efficiency.
- This finding supports a model where T cell selection is influenced by peptide-MHC availability.