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Editing autoreactive TCR enables efficient positive selection.
Fabio R Santori1, Ivica Arsov, Mirjana Lilić
1Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|August 8, 2002
Summary
Inefficient allelic exclusion allows T cells to express two T cell receptors (TCRs). Editing autoreactive TCRs enhances positive selection, potentially explaining the survival of T cells with dual TCRs and mitigating autoimmunity risks.
Area of Science:
- Immunology
- T cell biology
- Autoimmunity
Background:
- Allelic exclusion is often inefficient at the T cell receptor alpha (TCRalpha) locus.
- This inefficiency allows a significant proportion of T cells to express two functional TCRs.
- Dual TCR expression poses a risk of rescuing autoreactive TCRs during thymic selection, potentially leading to autoimmunity.
Purpose of the Study:
- To investigate the reasons behind replacing autoreactive TCRs.
- To understand the mechanisms allowing T cells with dual TCRs to survive.
- To explore the relationship between autoreactive TCR editing and T cell development.
Main Methods:
- Comparison of TCR transgenic CD4(+)CD8(-) thymocyte development in the presence and absence of MHC class II autoantigen.
- Utilizing autoantigen that does not induce thymocyte deletion.
- Employing a human CD4 transgene to modulate autoantigenic signal strength.
Main Results:
- The presence of MHC class II autoantigen led to approximately 100% more CD4(+)CD8(-) thymocytes compared to a neutral background.
- Increased autoantigenic signal strength via human CD4 transgene expression resulted in a further rise in CD4(+)CD8(-) thymocyte numbers.
- Contrary to expectations, autoantigen presence enhanced thymocyte development.
Conclusions:
- Editing autoreactive TCRs leads to more efficient positive selection.
- This enhanced selection may serve as a reason and a reward for T cells risking autoimmunity.
- The findings suggest a mechanism where TCR editing balances self-tolerance and T cell repertoire development.