Anti-Tumor Immune Response. Image courtesy of the National Cancer Institute.
How do T cells, the beat cops of the immune system, detect signs of disease without the benefit of eyes? Like most cells, they explore their surroundings through direct physical contact, but how T cells feel out intruders rapidly and reliably enough to nip infections and other threats in the bud has remained a mystery to researchers.
In a new study, published online May 11, 2017 in Science, UC San Francisco researchers began to address this question by using cutting-edge techniques to capture videos of the surface of living T cells in more detail than ever before. Researchers had previously observed tentacle-like protrusions called microvilli covering the surface of T cells, but the new research revealed that these tentacles are in constant motion: they crawl across the cell surface, each independently searching for signs of danger or infection in a fractal-like pattern that allows T cells to spend the minimum time necessary feeling for a potential threat before moving on.
“Previous techniques had allowed us to take snapshots of the surface of T cells, but that’s like trying to understand a basketball game by studying a black-and-white photo,” said Matthew Krummel, PhD, associate professor of pathology at UCSF and senior author of the new study. “Now we can watch these amazing little fingers of membrane move around in real-time – and it turns out they’re incredibly efficient."
Among other potential benefits, Krummel says, understanding how T cells efficiently sample their environment to search for invasive pathogens opens up new questions about what countermeasures infectious organisms or even cancer cells may have evolved as a way of avoiding detection, and could suggest new ways for researchers to help T cells see through such a ruse.
Efficient Search by T Cells is Key to an Effective Immune Response
As they make their rounds through the body, T cells make contact with a network of informants — other immune cells that scour the body for potential signs of danger and display the protein fragments they find (called “antigens”) on their surface for inspection by the T cells. If a T cell meets one of these so-called antigen-presenting cells and recognizes a protein fragment it carries as evidence of danger, the T cell sounds the alarm and triggers a more global immune response to fight off the invaders.
Scientists estimate that you have only about 100 T cells in your body at any given moment that can recognize and responding to a specific antigen, such a protein from this year's flu virus, and these few cells each take days to patrol your entire body, Krummel said. "This means the immune system really needs to get ahead of whatever is attacking the body at the very first evidence that there’s an intruder on board. If one T cell misses the signs of a virus, the next time a cell that can recognize the threat might come through that tissue, the virus has had hours to make tens of thousands of copies of itself."
New Imaging Reveal How Immune Cells “Talk”
In the Science study, Krummel’s team was able to study how T cells efficiently interrogate antigen-presenting cells in real time, thanks to a high-resolution cellular imaging technique called lattice light-sheet microscopy, which the team set up at UCSF in collaboration with its inventor, 2014 Nobel prize winner and study co-author Eric Betzig, PhD, of the Howard Hughes Medical Institute’s Janelia Research Campus in Virginia.