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High-Efficiency Generation of Antigen-Specific Primary Mouse Cytotoxic T Cells for Functional Testing in an Autoimmune Diabetes Model

High-Efficiency Generation of Antigen-Specific Primary Mouse Cytotoxic T Cells for Functional Testing in an Autoimmune Diabetes Model

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Optimal T-cell receptor affinity for inducing autoimmunity.

Sabrina Koehli¹, Dieter Naeher¹, Virginie Galati-Fournier¹

¹Departments of Biomedicine and Nephrology, University Hospital Basel and University of Basel, CH-4031 Basel, Switzerland;

Proceedings of the National Academy of Sciences of the United States of America

|November 21, 2014

Summary

This summary is machine-generated.

T-cell receptor (TCR) affinity for self-antigens influences self-tolerance. TCRs with affinity just above the negative selection threshold increase the risk of developing autoimmune diseases like diabetes.

Keywords:

T cell TCR affinity autoimmunity tolerance

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Area of Science:

Immunology
Autoimmunity
T-cell biology

Background:

T-cell receptor (TCR) affinity for self-antigen is crucial for maintaining self-tolerance.
Dysregulation of T-cell responses can lead to autoimmune diseases.

Purpose of the Study:

To investigate how varying T-cell receptor (TCR) affinity for self-antigen impacts negative selection efficiency.
To determine the relationship between TCR affinity and the propensity to induce autoimmune responses.
To assess the effect of TCR affinity on the elimination of self-reactive T cells.

Main Methods:

Generation of three transgenic mouse strains with T-cell receptors (TCRs) exhibiting variable affinities for a specific self-antigen (OVA).
Assessment of negative selection efficiency in response to different antigen affinities.
Evaluation of the potential to prime autoimmune responses and eliminate target cells.

Main Results:

Mice expressing self-antigens with TCR affinity just above the negative selection threshold showed the highest risk for experimental autoimmune diabetes.
Self-reactive T cells that narrowly escape deletion due to near-threshold affinity pose a significant risk for autoimmunity.
TCR affinity critically influences the balance between T-cell tolerance and autoimmune activation.

Conclusions:

T-cell receptor affinity plays a pivotal role in the development of autoimmunity.
A narrow window of TCR affinity, just above the negative selection threshold, is associated with an increased risk of autoimmune disease.
Understanding TCR affinity thresholds is key to predicting and potentially preventing autoimmune conditions.