Intrinsic immune receptor triggering mechanism informs rational chimeric receptor design

CD3ε is identified as a triggering subunit in TCR activation, with its intracellular domain released from the plasma membrane and forming phase-separated condensates that amplify signaling.

• Why it matters: The primary subunit that initiates the coordinated, eight-part TCR signaling event is unresolved, limiting mechanistic understanding and rational receptor engineering.
• What they did: The study shows that increased membrane tension promotes a membrane-proximal to membrane-distal transition, enabling CD3ε ICD condensates with Lck that recruit additional CD3ε ICDs; the CD3ε ICD alone supports robust activation independently of its ITAM.
• The result: A similar triggering mechanism is observed for several activating receptors in T and NK cells, enabling TRIG chimeric molecules that recruit endogenous receptors ligand-dependently and efficiently activate both cell types.

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