Cell子刊封面：许琛琦/施小山/王皞鹏合作揭示TCR信号多样性的脂质静电调控机制

Core Viewpoint - The research published in Molecular Cell reveals the phosphorylation hierarchy of the T cell receptor (TCR) CD3 complex, highlighting the role of lipid interactions in regulating TCR signaling diversity and suggesting that insufficient phosphorylation of CD3ζ may lead to T cell functional exhaustion [2][3]. Group 1 - The study utilized nuclear magnetic resonance, quantitative mass spectrometry, and cellular experiments to analyze the intracellular structure and phosphorylation patterns of the key signaling subunit CD3ζ in the TCR-CD3 complex [3]. - The research indicates that the basic residue-rich sequence (BRS) interacts with lipids, which is crucial for the regulation of TCR signaling [3]. - The findings suggest that chronic TCR stimulation, associated with cancer and chronic infections, leads to a faster decay of phosphorylation at the C-terminal ITAM compared to the N-terminal ITAM, resulting in insufficient TCR signaling [6][7]. Group 2 - The core findings of the study include the observation that the membrane insertion of ITAMs increases from the N-terminus to the C-terminus, and phosphorylation occurs sequentially from ITAM1 to ITAM3 under physiological stimulation [7]. - Mutations in the CD3ζ BRS eliminate the hierarchical phosphorylation of ITAMs, indicating the importance of this sequence in TCR signaling [7]. - The study provides new insights into the heterogeneity of ITAM phosphorylation in TCR signaling, which is relevant to both physiological and pathological conditions [6][7].