Super-resolution microscopy IDs molecular mechanism that drives immune response

Using super-resolution fluorescence microscopy, researchers at the University of New South Wales have been able for the first time to see the inner workings of T cells, which alert the immune system's defenses against germs and other invaders in the bloodstream.

Using super-resolution fluorescence microscopy, researchers at the University of New South Wales (UNSW; Sydney, Australia) have been able for the first time to see the inner workings of T cells, which alert the immune system's defenses against germs and other invaders in the bloodstream. The findings identify the exact molecular 'switch' that spurs T cells into action, which could lead to treatments for autoimmune diseases and cancer, among others.

Studying a cell protein important in early immune response, the researchers—led by Associate Professor Katharina Gaus from UNSW's Center for Vascular Research at the Lowy Cancer Research Center—used Australia's only microscope capable of super-resolution fluorescence microscopy to image the protein molecule by molecule to reveal the immunity 'switch.'

Using the new microscope, the scientists were able to image molecules as small as 10 nm. Gaus says that what the team found overturns the existing understanding of T cell activation—that T cell signaling was initiated at the cell surface in molecular clusters that formed around the activated receptor. Small membrane-enclosed sacs called vesicles inside the cell travel to the receptor, pick up the signal and then leave again, she says.

Explaining how the immune response could occur so quickly, Gaus says that the "signaling station is like a docking port or an airport with vesicles like planes landing and taking off. The process allows a few receptors to activate a cell and then trigger the entire immune response."

David Williamson, a Ph.D. candidate whose research formed the basis of the paper, said the discovery showed what could be achieved with the new generation of super-resolution fluorescence microscopes.

"In conventional microscopy, all the target molecules are lit up at once and individual molecules become lost amongst their neighbors—it's like trying to follow a conversation in a crowd where everyone is talking at once. With our microscope we can make the target molecules light up one at a time and precisely determine their location while their neighbors remain dark. This 'role call' of all the target molecules means we can then build a 'super resolution' image of the sample," says Williamson.

The next step was to pinpoint other key proteins to get a complete picture of T cell activity and to extend the microscope to capture 3-D images with the same unprecedented resolution.

"Being able to see the behavior and function of individual molecules in a live cell is the equivalent of seeing atoms for the first time. It could change the whole concept of molecular and cell biology," says Williamson.

The findings are reported in the journal Nature Immunology.

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Posted by Lee Mather

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