Scientists Use Super Microscope to Pinpoint Body’s Immunity 'Switch'
ScienceDaily (June 7, 2011) — Using the only microscope of its kind in Australia, medical scientists have been able for the first time to see the inner workings of T-cells, the front-line troops that alert our immune system to go on the defensive against germs and other invaders in our bloodstream.
Image of a single activated T cell -- From left to right: First, a conventional blurry image, where subcellular structures cannot be identified. Then, a super-resolution single molecule image with each white dot being exactly one protein. Next, an algorithm is applied to identify protein clusters (color indicates degree of cluster). Finally, identification of T cell signalling complexes, which can now be quantified. (Credit: Image courtesy of Dr. Katharina Gaus, Centre for Vascular Research, University of New South Wales)
The discovery overturns prevailing understanding, identifying the exact molecular 'switch' that spurs T-cells into action -- a breakthrough that could lead to treatments for a range of conditions from auto-immune diseases to cancer.
The findings, by researchers at the University of New South Wales (UNSW), are reported in the journalNature Immunology.
Studying a cell protein important in early immune response, the researchers led by Associate Professor Katharina Gaus from UNSW's Centre for Vascular Research at the Lowy Cancer Research Centre, used Australia's only microscope capable of super-resolution fluorescence microscopy to image the protein molecule-by-molecule to reveal the immunity 'switch'.
The technology is a major breakthrough for science, Dr Gaus said. Currently there are only half a dozen of the 'super' microscopes in use around the world.
"Previously you could see T-cells under a microscope but you couldn't see what their individual molecules were doing," Dr Gaus said.
Using the new microscope the scientists were able to image molecules as small as 10 nanometres. Dr Gaus said that what the team found overturns the existing understanding of T-cell activation.
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Pre-existing clusters of the adaptor Lat do not participate in early T cell signaling events
David J Williamson, Dylan M Owen, Jérémie Rossy, Astrid Magenau, Matthias Wehrmann, J Justin Gooding & Katharina Gaus
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Nature Immunology (2011) doi:10.1038/ni.2049
Received 25 February 2011 Accepted 05 May 2011 Published online 05 June 2011
Abstract
Engaged T cell antigen receptors (TCRs) initiate signaling through the adaptor protein Lat. In quiescent T cells, Lat is segregated into clusters on the cell surface, which raises the question of how TCR triggering initiates signaling. Using super-resolution fluorescence microscopy, we found that pre-existing Lat domains were neither phosphorylated nor laterally transported to TCR activation sites, which suggested that these clusters do not participate in TCR signaling. Instead, TCR activation resulted in the recruitment and phosphorylation of Lat from subsynaptic vesicles. Studies of Lat mutants confirmed that recruitment preceded and was essential for phosphorylation and that both processes were independent of surface clustering of Lat. Our data suggest that TCR ligation preconditions the membrane for vesicle recruitment and bulk activation of the Lat signaling network.
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