Themis sets the signal threshold for positive and negative selection in T-cell development

Area of Science:

• Immunology
• Molecular Biology
• Cell Biology

Background:

• T-cell receptor (TCR) signaling is crucial for developing a self-tolerant T-cell repertoire.
• T-cell development in the thymus involves positive and negative selection based on TCR affinity to self-peptides presented by MHC proteins.
• Low-affinity interactions promote positive selection, while high-affinity interactions lead to negative selection or agonist selection.

Purpose of the Study:

• To investigate the role of the T-cell-specific protein Themis in regulating TCR signal strength during T-cell development.
• To elucidate the mechanism by which Themis influences positive selection of T cells.

Main Methods:

• Investigated Themis's function in TCR signal attenuation.
• Examined Themis's interaction with SHP1.
• Analyzed the impact of Themis on TCR affinity thresholds for T-cell selection.

Main Results:

• Themis specifically attenuates TCR signal strength in response to low-affinity TCR engagement, but not high-affinity engagement.
• Themis functions as an analog-to-digital converter, translating graded TCR affinity into distinct selection outcomes.
• Themis dampens mild TCR signals, raising the affinity threshold for T-cell activation and enabling positive selection of naive T cells.

Conclusions:

• Themis is essential for positive selection of T cells by fine-tuning TCR signal strength.
• Themis ensures the development of a functional T-cell repertoire capable of recognizing pathogens while maintaining self-tolerance.