Lipid-gated “phosphorylation code” for TCR graded signaling and T-cell exhaustion

The TCR/CD3s complex translates antigenic cues into graded immune responses. Xu and colleagues (Molecular Cell, 2025) revealed a lipid-electrostatic mechanism that governs sequential phosphorylation of the CD3ζ chain. Using NMR in a membrane-mimetic system, they uncovered a gradient of membrane insertion across its ITAMs, establishing a structural basis for tunable signaling. Under chronic stimulation, ATP depletion preferentially impairs distal ITAM phosphorylation, revealing an intrinsic energy-sensitive pathway driving T cell exhaustion. These findings provide a compelling model for TCR regulation and suggest strategies to enhance immunotherapy via CD3ζ engineering or metabolic restoration.