Adaptable TCR avidity thresholds for negative selection

Area of Science:

• Immunology
• Autoimmunity
• T cell biology

Background:

• Central tolerance is crucial for preventing autoimmune diseases.
• T cells with high avidity for self-antigens are typically eliminated.
• The precise mechanisms governing the threshold for T cell deletion remain incompletely understood.

Purpose of the Study:

• To investigate the adaptability of the T cell deletion threshold.
• To determine how globally increased T cell receptor (TCR) avidity impacts central tolerance.
• To explore the consequences of altered T cell selection on autoimmune disease development.

Main Methods:

• Creation of a unique transgenic mouse model with globally increased TCR avidity for self-peptide/MHC complexes.
• Analysis of T cell populations, including TCR levels and CD5 expression.
• Assessment of experimental allergic encephalomyelitis and lupus severity.
• Evaluation of natural regulatory T cell numbers and activity.

Main Results:

• Transgenic mice exhibited more severe experimental allergic encephalomyelitis and lupus.
• Despite adaptations to reduce T cell reactivity (e.g., reduced TCR levels, increased CD5), self-reactive T cells persisted.
• Natural regulatory T cell numbers and activity remained unchanged.
• The threshold for T cell deletion was shown to be adaptable.

Conclusions:

• The threshold for T cell deletion is not fixed and can be adjusted.
• Globally increased TCR avidity allows the survival of T cells with higher self-reactivity.
• Altered central tolerance contributes to the development of autoimmune diseases.