T cells’ dynamic, finger–like projections efficiently search for signs of infection, study shows.
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 the journal 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."

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 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.

In this 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.

Using this technology, the team studied mouse T cells exploring simulated patches of antigen–presenting cell membrane in laboratory dishes, and found that the T cell microvilli move independently of one another in a fractal–like geometry, such as is often seen in nature as a way of optimizing efficient use of space, such as by plant roots or foraging animals.

The researchers calculated that, thanks to this efficient search pattern, in an average minute–long encounter win an antigen–presenting cell, T cell microvilli can thoroughly explore 98 percent of the contact surface between the two cells – called an “immunological synapse” after the neuronal synapses of the nervous system. This suggests that T cells are tuned to spend the minimum time necessary to get a clear read on the information available at each antigen–presenting cell before moving on, the authors say.