Unexpected immune activation illustrated in the cold
Researchers at Utrecht University and Leiden University Medical Center, the Netherlands, have imaged an important immune system on-switch. Their novel technical approach has led to the discovery of two ways in which the immune system can be activated. This is important for designing better therapies for infections or cancer, according to team leaders Piet Gros and Thom Sharp. Their findings are published in Science.
When the immune system detects invading microbes, viruses and tumours, antibodies engage in an immediate defence strategy, alerting the body's immune system of a security breach. This is the entry cue for several molecules, together called the C1 complex, that stick to the surface of the rogue cell and eliminate it. Until recently, it was not known exactly how invaders were recognized, or how this C1 complex was activated.
Studying the C1 complex is challenging since its components often clump together when taken out of their natural environment into a lab setting. Together with the international biotech company Genmab A/S, researchers from Utrecht University and Leiden University Medical Center have now developed a unique technical approach to studying it in a more natural environment—and discovered more than expected.
In order to capture the binding and interaction of the complex, Piet Gros, Utrecht University and Thom Sharp, Leiden University Medical Center, combined two imaging techniques, cryo electron microscopy (CryoEM) and cryo electron tomography (CryoET). "These technologies are exploding in the field," says Thom Sharp. "Each method gives us different but complementary information on the same complex." When combined, these methods provide a more life-like detailed picture of the system.
CryoEM basically entails scattering thousands of copies of the same convoluted complex onto the sticky side of a piece of tape. The camera is in a fixed position and takes pictures of these particles, which may have landed in any orientation. CryoET, on the other hand, can image the complex in a more natural environment, as it is bound to the cell surface. It takes images from different angles of the complex, similar to a CT scan, where the particle rotates within the instrument. For both techniques, the images are then reconstructed into a 3-D representation of the complex.
The researchers were surprised to find two ways in which the immune system can be activated—by physical distortion and by cross-activation. In some cases, the configuration of danger signals on a cell's surface is sparse, and when antibodies bind, the entire complex must physically adjust or distort itself to fit properly. This adjustment of a single complex can set off an immune response. In other situations, where the danger signals are dense, multiple C1 complexes can help activate each other, like a neighbourhood watch system.
This is the first report of two independent means by which the immune system can be activated. In addition, the combination of CryoEM and CryoET enabled the visualization of details of these interactions that may lead to more specific therapeutics that can activate, slow down or stop the cascade of signals within the immune system.