🎯 A never-before-seen view of our killer cells in action

Cytotoxic T lymphocytes are the body's specialized "killers", precisely eliminating infected or cancerous cells. Their action relies on a specialized exchange zone called the "immune synapse", where they release active molecules to destroy the target cell without damaging neighboring ones.

Until now, the fine organization of these structures remained difficult to observe. A study led by the University of Geneva (UNIGE) and the Lausanne University Hospital (CHUV) made it possible to visualize these mechanisms in three dimensions in a near-native state. Published in Cell Reports, the study reveals how the molecular organization of cytotoxic T cells underpins their function, opening new perspectives in immuno-oncology.


During an infection or cancer, cytotoxic T lymphocytes adhere to their target and establish an exchange zone called the "immune synapse", then release toxic molecules that trigger the death of the targeted cell. This mechanism allows precise and controlled destruction, essential for protecting the body while avoiding damage to neighboring healthy cells.

By providing a three-dimensional and near-native view of these processes, this work establishes a reference framework for analyzing the functioning of immune cells.

Although this process is widely studied, its nanoscale organization in intact human cells remained difficult to access. One of the main obstacles is sample preparation methods, which can alter fragile cellular structures. Existing imaging approaches often involve trade-offs between resolution, observable volume, and preservation of structures.

A technique to see the invisible

To overcome these limitations, a study by UNIGE and CHUV-UNIL, supported by the TANDEM program of the ISREC Foundation, relied on cryo-expansion microscopy (cryo-ExM).

"This technique consists of instantly freezing the cells by cooling them at very high speed, placing them in a so-called vitreous state, where water solidifies without forming crystals and thus faithfully preserves biological structures. The samples are then physically enlarged using an absorbent hydrogel, allowing their internal organization to be observed with high precision while preserving their near-native architecture," explains Virginie Hamel, senior lecturer and researcher at the Department of Molecular and Cellular Biology of the Faculty of Science at UNIGE.


"Our work reveals that at the point of contact between the immune cell and its target, the membrane forms a kind of dome, whose structure appears linked to adhesion interactions and the internal organization of the cell," stresses Florent Lemaître, postdoctoral fellow at the Department of Molecular Biology of the Faculty of Science at UNIGE and first author of the study.

The research team also visualized with an unprecedented level of detail the cytotoxic granules responsible for destroying target cells. It reveals that these structures can vary in their organization, with one or more "cores" that concentrate the active molecules to destroy the target cell.

From cells to patients

"We extended this approach to human tumor tissues, allowing direct observation of tumor-infiltrating T lymphocytes and their cytotoxic machinery at the nanoscale. This makes it possible to study immune responses directly in their clinical context and better understand the mechanisms that determine their effectiveness," explains Benita Wolf, senior physician and associate researcher at the Department of Clinical Oncology at CHUV, who co-directed the study.

By providing a three-dimensional and near-native view of these processes, this work establishes a reference framework for analyzing the functioning of immune cells. They could help improve therapeutic strategies, particularly in immuno-oncology, by allowing a better understanding of the mechanisms that determine the effectiveness — or limitations — of the immune response.