Discovery Illuminates How T Cell Receptors Activate Immune Defenses

A team at The Rockefeller University has uncovered how T cell receptors (TCRs) change shape when activated, providing long-sought insight into a central mechanism underpinning T cell immunotherapies. These treatments, which harness a patient’s immune system to target cancer, have shown remarkable success for certain cancer types but limited benefit for many others. Understanding how T cells recognize and respond to abnormal cells could help refine these therapies and extend their reach.

Using cryo-electron microscopy, the team visualized the TCR in a near-native environment. They discovered that the receptor behaves like a “jack-in-the-box,” remaining closed until it encounters an antigen, at which point it springs open. This finding, published in Nature Communications, overturns previous structural models that depicted the receptor as permanently open.

“This new fundamental understanding of how the signaling system works may help re-engineer that next generation of treatments,” says first author Ryan Notti.

The TCR sits in the cell membrane and enables T cells to identify antigen fragments displayed by human leukocyte antigen (HLA) molecules. Recognizing these signals prompts immune activation. However, the earliest steps in T cell receptor activation had not been clearly observed. Notti proposed investigating this process using biochemical environments that mimic real cell membranes, an approach pioneered by senior author Thomas Walz. 

Walz’s group designed custom nanodiscs—tiny pieces of membrane stabilized by a scaffold protein—that closely replicated the TCR’s natural conditions. “Getting all eight of these proteins properly assembled into the nanodisc was challenging,” Notti says. Imaging revealed that the receptor remains compact when inactive but opens widely after encountering an antigen-presenting molecule.

Walz explains that prior studies used detergent, which stripped away the membrane and disrupted the receptor’s resting state. “It was important that we used a lipid mixture that resembled that of the native T cell membrane,” he says. “If we had just used a model lipid, we wouldn’t have seen this closed dormant state either.” 

The researchers believe these insights may guide improvements in T cell therapies and vaccine development. “People in the field can now use our structures to see refined details about the interactions between different antigens presented by HLA and T cell receptors. Those different modes of interaction might have some implication for how the receptor functions—and ways to optimize it,” Walz notes.