Cutting Edge: Low-Affinity TCRs Support Regulatory T Cell Function in Autoimmunity

Area of Science:

• Immunology
• Autoimmunity
• T cell biology

Background:

• Regulatory T cells (Tregs) possess a unique TCR repertoire and heightened self-reactivity compared to conventional T cells.
• The precise role of TCR affinity in modulating the function of self-reactive Tregs remains largely uncharacterized.

Purpose of the Study:

• To investigate the impact of TCR affinity on Treg function in the context of autoimmune diabetes using a two-TCR model.
• To elucidate the distinct functional profiles of high- and low-affinity Tregs during autoimmune responses.

Main Methods:

• Utilized a two-TCR model to simulate distinct TCR affinities in regulatory T cells.
• Assessed Treg recruitment to the pancreas and evaluated the expression of key functional mediators.

Main Results:

• Both high- and low-affinity Tregs were recruited to the pancreas and conferred protection against autoimmune diabetes.
• High-affinity Tregs preferentially upregulated IL-10, TIGIT, GITR, and CTLA4.
• Low-affinity Tregs showed increased expression of Areg and Ebi3, indicating divergent functional pathways.

Conclusions:

• TCR affinity plays a critical role in shaping Treg function during autoimmunity.
• Distinct functional profiles of high- and low-affinity Tregs suggest mechanistically separate and potentially nonredundant roles in controlling autoimmune diabetes.