Researchers at The Rockefeller University and Memorial Sloan Kettering Cancer Center have revealed a hidden spring‑like motion in the T cell receptor that helps trigger immune responses. Observed with cryo‑electron microscopy in a native‑like membrane environment, the mechanism may help explain why some T cell–based immunotherapies succeed while others fall short, and could inform efforts to make such treatments work for more patients.
T cell–based immunotherapies have emerged over the past decade as one of the most promising advances in cancer treatment, harnessing a patient's own immune system to recognize and destroy malignant cells. Yet these therapies currently benefit only a subset of cancers and patients, leaving open questions about the underlying molecular machinery that controls T cell activation.
In new work from Thomas Walz’s Laboratory of Molecular Electron Microscopy at The Rockefeller University, scientists used cryo‑electron microscopy (cryo‑EM) to examine the human T cell receptor–CD3 (TCR–CD3) complex, a membrane protein assembly on T cells that detects antigens presented by human leukocyte antigen (HLA) molecules on other cells. According to Rockefeller University, the team embedded the TCR–CD3 complex in nanodiscs—tiny disc‑shaped synthetic membranes that closely mimic the native lipid environment—allowing them to visualize the receptor in conditions resembling those inside a living cell.
Previous structural studies of the TCR–CD3 complex often relied on detergents to extract the receptor from the cell membrane, which can strip away surrounding lipids and influence the protein’s conformation. In contrast, the nanodisc‑based approach revealed that in its resting, unliganded state the membrane‑embedded TCR–CD3 adopts compact, closed conformations, rather than the open and extended shape seen in detergent preparations.
When the complex binds an HLA molecule presenting an antigen, however, the structure opens and extends outward. The researchers describe this as a kind of spring‑loaded motion, akin to a jack‑in‑the‑box, that accompanies activation of the receptor and helps initiate signaling inside the T cell. These allosteric conformational changes, reported in Nature Communications, had not been directly observed in the receptor’s native‑like membrane environment before and challenge earlier depictions of the TCR as being constitutively open.
“This new fundamental understanding of how the signaling system works may help re‑engineer that next generation of treatments,” said first author Ryan Notti, an instructor in clinical investigation in Walz’s lab at Rockefeller and a special fellow in the Department of Medicine at Memorial Sloan Kettering Cancer Center, where he treats patients with sarcomas, or cancers that arise in soft tissue or bone, according to Rockefeller and ScienceDaily.
“The T cell receptor is really the basis of virtually all oncological immunotherapies, so it’s remarkable that we use the system but really have had no idea how it actually works—and that’s where basic science steps in,” added Walz, a cryo‑EM expert who leads the laboratory, in comments reported by Rockefeller University.
By comparing the closed resting and open ligand‑bound states of the TCR–CD3 complex in nanodiscs, the authors showed that ectodomain opening is necessary for maximal ligand‑dependent T cell activation. The structures also reveal conformation‑dependent interactions between the receptor, surrounding lipids, and attached glycans, underscoring the importance of studying membrane proteins in environments that preserve their native lipid context.
The findings, published on December 16, 2025, in Nature Communications, suggest concrete avenues for improving T cell–based therapies. Notti noted that adoptive T cell therapies—treatments in which patients receive T cells engineered to recognize cancer antigens—are already being used successfully against certain rare sarcomas, and that tuning the receptor’s activation threshold based on these structural insights might help broaden their impact. Walz said the work could also aid vaccine design by providing higher‑resolution views of how different HLA‑presented antigens engage T cell receptors and influence their function.
While translating these basic structural discoveries into new drugs or cell therapies will require substantial additional research, the study provides a detailed molecular framework for understanding how T cell receptors switch from an inactive, closed state to an active, extended state in response to antigen binding—an insight that could ultimately help make immunotherapies more precise and more widely effective.
