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RAG-dependent peripheral T cell receptor diversification in CD8+ T lymphocytes.
Pau Serra1, Abdelaziz Amrani, Bingye Han
1Department of Microbiology and Infectious Diseases, and Julia McFarlane Diabetes Research Centre, Faculty of Medicine, Health Sciences Centre, University of Calgary, 3330 Hospital Drive N.W., AB, Canada T2N 4N1.
Summary
Mature T cells can reexpress V(D)J recombination-activating genes (RAGs), leading to new T cell receptor (TCR) rearrangements. This discovery challenges the dogma that RAG expression permanently ceases after T cell development, suggesting a mechanism for peripheral T cell repertoire diversification.
Area of Science:
- Immunology
- Molecular Biology
- T cell biology
Background:
- T cell receptor (TCR) gene rearrangement is mediated by V(D)J recombination-activating genes (RAGs).
- Conventional understanding posits that RAG expression is permanently silenced in mature T cells exiting the thymus.
Purpose of the Study:
- To investigate whether mature T cells can reexpress RAGs and diversify their TCR repertoire outside the thymus.
- To explore the implications of RAG reexpression for T cell receptor specificity and function.
Main Methods:
- Stimulation of CD8(+) T cells from nonobese diabetic (NOD) mice and TCR-transgenic mouse models with peptide-pulsed dendritic cells.
- Analysis of RAG gene expression, TCR repertoire, and cell surface marker expression.
Main Results:
- Repeated stimulation induced RAG reexpression in peripheral CD8(+) T cells.
- Reexpressing T cells lost specificity for their original peptide target and acquired diverse TCR rearrangements.
- RAG reexpression was observed in specific CD8(+) T cell subsets in NOD mice and certain TCR-transgenic models, but not universally.
Conclusions:
- Extra-thymic RAG reexpression in specific CD8(+) T cell populations allows for further diversification of the peripheral T cell repertoire.
- This finding challenges established immunological dogma regarding T cell receptor stability and offers new insights into immune system adaptability.