Self-programmed dynamics of T cell receptor condensation

Area of Science:

• Immunology
• Cell Biology
• Biophysics

Background:

• Receptor-ligand engagement triggers cell surface receptor clustering, forming signaling hubs that regulate cellular events.
• These dynamic clusters are often transient, disassembling to terminate signaling, but the regulatory mechanisms remain unclear.
• T cell receptors (TCRs) form dynamic clusters for robust yet temporal signaling essential for adaptive immunity.

Purpose of the Study:

• To investigate the mechanism controlling dynamic T cell receptor (TCR) clustering and signaling.
• To identify the role of phase separation in the formation and dissolution of TCR signaling hubs.

Main Methods:

• Investigated the phase separation mechanism of TCR clustering using biochemical and biophysical approaches.
• Analyzed the role of CD3ε chain condensation with Lck kinase in TCR signalosome formation.
• Examined the effect of Lck-mediated phosphorylation on CD3ε binding preference and signalosome dissolution.

Main Results:

• Identified phase separation as a key mechanism regulating dynamic TCR clustering and signaling.
• Demonstrated that the CD3ε chain condenses with Lck kinase to form TCR signalosomes for antigen signaling.
• Showed that Lck-mediated CD3ε phosphorylation promotes Csk binding, leading to signalosome dissolution and termination of signaling.
• Found that modulating TCR/Lck condensation impacts T cell activation and function.

Conclusions:

• Phase separation governs the dynamic assembly and disassembly of TCR signalosomes, acting as a built-in regulatory mechanism for T cell signaling.
• This self-programmed condensation and dissolution process is critical for controlling T cell activation and function.
• The identified phase separation mechanism may be relevant to the signaling dynamics of other cell surface receptors.