By making use of a new ‘super resolution’ microscope that provides sharp images at extremely small scale, scientists have obtained unprecedented views of the immune system in action. This new stimulated emission depletion (STED) microscope shows how granules within natural killer (NK) cells pass through openings in the dynamic cell skeleton to destroy their targets: tumor cells and cells infected by viruses. Deeper understanding of these biological events may allow scientists to devise more effective treatments for inherited diseases that impair the immune system.
“This new technology enables researchers to see individual elements previously below the physical limits of imaging using light,” said study leader Dr Jordan S. Orange, of the Children’s Hospital of Philadelphia. Previously, microscopes could not distinguish objects smaller than 200 nanometers (a nanometer is one millionth of a millimeter). The STED microscope uses a unique arrangement of lasers and fluorescence to image fine structures, such as protein filaments, smaller than 60 nanometers.
The new study is published Sept. 13 in the online, open-access journalPLoS Biology.
Orange has long researched the biology of NK cells at the immunological synapse — the site where the NK cell attaches to its target cell and delivers granules packed with molecules that, when released, perforate and kill the target cell. Before they can be released from the NK cell, these granules must pass through a dense network of filaments made of a protein called F-actin.
Previously, F-actin was thought to be absent from the center of the synapse where the granules fuse with the cell surface. With super-resolution microscopy, the new study of live human cells reveals that F-actin pervades the synapse, but leaves openings just large enough to allow granules to pass through. “At the same time, F-actin appears to be dynamically interacting with the granules to move them toward their targets,” Orange added.
Orange compared the F-actin filaments to the rails of a roller coaster, but one that quickly rearranges itself to guide the rider through a narrow tunnel. Further studies of NK function, Orange said, will investigate the mechanisms that allow lytic granules to navigate the immunological synapse. He added, “As we better understand how this process is regulated, we will work toward manipulating immune responses to treat immune deficiency disorders.”
The work was supported by US National Institutes of Health (NIH) grants R01AI067946 to JSO, and R01GM070898 and S10RR22482 to TS. GDR was supported by NIH training grant T32AR007442.
- Gregory D. Rak, Emily M. Mace, Pinaki P. Banerjee, Tatyana Svitkina, Jordan S. Orange. Natural Killer Cell Lytic Granule Secretion Occurs through a Pervasive Actin Network at the Immune Synapse. PLoS Biology, 2011; 9 (9): e1001151 DOI: 10.1371/journal.pbio.1001151