“Our work reveals that at the point of contact between the immune cell and its target, the membrane forms a kind of dome.” That is how Florent Lemaître, a postdoctoral researcher at the University of Geneva, describes what his team saw when it looked at killer T cells in three dimensions for the first time.
The work, from the University of Geneva (UNIGE) and Lausanne University Hospital (CHUV), appears in Cell Reports. Lemaître is first author.
The problem with looking closely
Cytotoxic T lymphocytes are the immune system’s specialized killers. They find infected or cancerous cells and destroy them while leaving healthy neighbors alone. The trick depends on a tight contact point called the immune synapse, where the T cell releases toxic molecules into its target.
Scientists have long understood the basics. Seeing the fine detail has been harder, because the usual sample preparation can distort delicate cell parts. Existing imaging forces a choice between high resolution, a wide field of view, or keeping the cell’s natural structure intact.
Freeze, then expand
The team, supported by the ISREC Foundation TANDEM program, used a method called cryo-expansion microscopy, or cryo-ExM. Virginie Hamel, a Senior Lecturer in UNIGE’s Department of Molecular and Cellular Biology, explains it this way: cells are frozen instantly at very high speed into a glassy state, where water solidifies without forming crystals. That preserves biological structures. An absorbent hydrogel then physically expands the sample, so its internal layout can be seen with great precision.
The dome-shaped membrane was one result. Lemaître says its structure appears to be linked to adhesion interactions and to the cell’s internal organization.
The researchers also looked closely at the cytotoxic granules that do the killing. These turned out to vary. Some contain a single “core” where the active molecules are concentrated, and others hold several.
Into real tumors
The group did not stop at isolated cells. They applied the method to human tumor samples. “This allows us to study immune responses directly in their clinical context and to better understand the mechanisms that determine their effectiveness,” said Benita Wolf, Chief Resident and Associate Researcher in the Department of Clinical Oncology at CHUV, who co-led the study.
T lymphocytes infiltrating a tumor, and their killing machinery, can now be observed at the nanometer scale. The researchers say that better knowledge of what drives successful immune attacks on cancer, and what limits them, could help refine immuno-oncology treatments.
