T cells discriminate “self” from “non-self” and protect us from diseases. Their T cell receptor (TCR) works as a key transducer to convert the outside antigen signal into an inside action signal, kicking off the immune responses. This conversion is mediated by tiny segments called ITAMs in the TCR inner part. When they receive small chemical tags, called phosphorylation, signals start. With many ITAMs, T cells can mix and match tags to make the appropriate response against different dangers.
In a study published in Molecular Cell, a research team led by Prof. XU Chenqi from the Center for Excellence in Molecular Cell Science (Shanghai Institute of Biochemistry and Cell Biology) of the Chinese Academy of Sciences, collaborated with Prof. SHI Xiaoshan from Shenzhen Institutes of Advanced Technology, CAS, and Prof. WANG Haopeng from ShanghaiTech University. They uncovered two key things: first, the ITAMs in CD3ζ (a key part of the TCR) have different structures and functions; second, how acidic lipids in cell membranes control these ITAMs through electric attraction with “BRS” patches in CD3ζ. They also found that CD3ζ’s ITAMs don’t get enough phosphorylation when T cells get tired, which makes T cells less able to fight.
There are a pair of CD3ζ molecules in the TCR complex. Each CD3ζ has 3 ITAMs, making up 60% of the TCR’s phosphorylation sites to send signals. That’s why CD3ζ is always used in CAR-T therapy (a treatment that trains T cells to kill cancer). Recent techniques like cryo-EM have shown how TCR’s outer and middle parts look like, but not its flexible inner parts. So how the TCR sends signals remained a mystery.
To solve this, the team used two tools: a “bicelle” system mimicking the acidic cell membrane, and solution Nuclear Magnetic Resonance (NMR) spectroscopy that “sees” flexible molecular shapes. They found that the three ITAMs in CD3ζ stick into the cell membrane—but at different depths: ITAM1 is the shallowest, and ITAM3 the deepest. This depth difference comes from electric attraction between BRSs and membrane lipids, not from the ITAMs themselves.
Functionally, the deeper an ITAM sticks, the harder it is to get the phosphorylation tag. ITAM1 is the easiest to get a tag, so tags go from ITAM1 to ITAM3. When T cells face long-term threats like cancer or infections, they run low on energy. Then the tagging of ITAM3 breaks down faster than that of ITAM1, leaving CD3ζ with only some tags. So the TCR’s own weak signals from not enough tags also play a role, and not only external blocks like PD-1 or LAG3 cause tired T cells.
By mixing three sciences (biophysics, biochemistry and immunology), the study explains how lipids control ITAM tags and reveals a new way T cells get tired. This helps develop better immunotherapies. The paper was selected as the cover story (Figure 1). The picture shows CD3ζ as a 6-hole flute: different hole combinations make different sounds, just like how different ITAM tags create different immune responses. It was drawn by ZHANG Yumeng from XU Chenqi’s team.
Reference: https://www.cell.com/molecular-cell/fulltext/S1097-2765(25)00746-4
Appendix：
