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In a new study led by Professor Mike Dustin at the Kennedy Institute, and the team lead Dr. Alexander Leithner (now at the University of Salzburg, Austria), in collaboration with Audun Kvalvaag, at the Institute for Cancer Research at the University Hospital Oslo, examined how the physical presentation of a protein called ICAM-1 (Intercellular Adhesion Molecule 1) on a target cells affects the activation of T cells — the immune system’s cells responsible for identifying and eliminating infected or cancerous cells.
Published in PNAS, their findings show that when ICAM-1 is locked in place, rather than free to move within the cell membrane, T cells show a stronger response and become more effective at killing target cells. The study provides new insight that could help design better immune strategies and may have implications for vaccine design, cancer immunotherapy and understanding immune evasion.
Proteins on the surface of cells are not fixed. Many float freely within the fluid lipid membrane of the cell’s outer layer. However, some proteins such as ICAM-1 can be locked in place by attaching to the underlying cell skeleton or cytoskeleton.
ICAM-1 is found on antigen-presenting cells, specialist immune cells which activate T cells by showing them fragments of pathogens or tumours. Previous research has shown that ICAM-1 tends to float freely on less effective antigen-presenting cells but is anchored to the cytoskeleton in the best performing ones.
‘We knew that ICAM-1 mobility was different in different cells,’ said Professor Dustin. ‘What we didn’t know was whether that physical difference alone could change how T cells behave. By manipulating ICAM-1 in live cells, other aspects of its function, such as signalling, may also change. So, our challenge was to find a way to isolate the effect of mobility alone.’
To allow them to isolate mobility as a single variable, the team engineered a highly controlled artificial surface that mimics key features of an antigen-presenting cell. In this way, they could precisely control whether ICAM-1 was mobile or immobilised, while keeping all other relevant components identical and freely mobile.
They found that anchoring ICAM-1 substantially altered cellular behaviour and showed significantly stronger T cell activation compared with surfaces where ICAM-1 could move freely. The researchers observed higher levels of activation markers and enhanced production of immune signalling molecules.
Further analysis suggested that this is due to a form of mechanically activated signalling (mechanotransduction) in the T cells. T cells exert physical forces when they engage with other cells. When ICAM-1 is anchored, it resists these forces which appears to trigger a form of mechanically activated signalling, known as mechanotransduction.
In effect, the T cell ‘pulls’ on ICAM-1 through its receptor LFA-1. If ICAM-1 is firmly anchored, that pulling generates stronger internal signals inside the T cell. If ICAM-1 moves freely, the mechanical resistance is reduced and signalling is weaker.
The team found that immobilised ICAM-1 altered the organisation of the ‘immunological synapse’ (IS), a highly organised cell-cell interface that governs critical T cell functions, including antigen recognition, signal integration and effector responses. The classical bull’s eye configuration that was hypothesized to enhance killing of target cells was blocked, yet targets cells were killed even better. These results require developing a new model for the immunological synapse.
The findings were confirmed in a more physiological cell–cell system. When target cells expressed full-length, cytoskeleton-anchored ICAM-1, they were killed more efficiently by T cells than cells expressing a version of ICAM-1 that could not anchor to the cytoskeleton.
Professor Dustin said: ‘Our study shows that the physical context in which immune receptors engage is not just background detail. It is part of the signal. It adds an important new dimension to our understanding of how T cells are activated and controlled. This has important implications for the design of vaccines and strengthening the immune response in viral infection and cancers.’