Protein & Cell, 24 December, 2025, DOI：https://doi.org/10.1093/procel/pwaf110

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

Hui Chen, Jizhong Lou, Wei Chen

Abstract

The T cell receptor (TCR)/CD3s complex represents one of the most sophisticated signaling machineries in immunology, capable of translating diverse antigenic stimulations into finely tuned cellular outcomes—ranging from activation and proliferation to differentiation and exhaustion, ultimately orchestrating T-cell fate transitions (Minguet et al., 2025). At the heart of this complex lies the CD3ζ chain, whose cytoplasmic domain contains three immunoreceptor tyrosine-based activation motifs (ITAMs). Remarkably, these ITAMs account for nearly 60% of all phosphorylatable tyrosine residues in the entire TCR/CD3s complex. Owing to its central role in propagating TCR signals, CD3ζ has also become a foundational component in chimeric antigen receptors (CAR) design, serving as the key signaling module that underpins the success of CAR-T cell therapies.

Article link：https://academic.oup.com/proteincell/advance-article/doi/10.1093/procel/pwaf110/8404448