New insight into how the immune system sounds the alarm

Now, scientists at the Salk Institute have discovered that T cell triggering relies on a dynamic protein network at the cell surface, as reported in August 3, 2015, in Nature Immunology.

"This is a completely new principle for how T cell activity is controlled--whether it ignores or responds to a threat," says senior author Björn Lillemeier, an assistant professor in the Nomis Foundation Laboratories for Immunobiology and Microbial Pathogenesis and the Waitt Advanced Biophotonics Center at the Salk Institute.

T cells become active when a signal--often from a virus or bacterium--triggers molecular sensors on their surface, namely T cell receptors. Previously, scientists believed that additional molecules that bind T cell receptors and help it to perceive this signal were like grapes hanging from a vine, occasionally dropping away or joining to begin the process. In contrast, the new discovery shows that T cell receptors are incredibly active--more like a bustling train station, with molecules rapidly coming and going at different intervals of time, says Lillemeier, who is also the Helen McLoraine Developmental Chair.

A protein called ZAP-70 is well known as a crucial player for kicking the T cell into action. Until now, scientists assumed that a silent form of ZAP-70 floats around inside the T cell until a threat is detected, which recruits ZAP-70 to the cell surface and activates it. By analyzing mutant forms of ZAP-70, Lillemeier's group discovered that instead of ZAP-70 binding the T cell receptor firmly, it comes in contact with the receptor sporadically. Each time this happens, ZAP-70 has to adopt an unfavorable shape that forces it back inside the cell. This cycle continues until a second molecule, called Lck, helps it to remain with the T cell receptor. The prolonged stay at the cell surface activates ZAP-70 and prompts the T cell to attack invaders and diseased cells.

This study shows that the steps underlying T cell activation are much more dynamic compared with the less mobile modes that scientists had suspected before. The new study highlights how ZAP-70 and other molecules communicate in space and time, which is crucial for controlling the ultimate activity of a T cell. By understanding this process, Lillemeier says, "We might be able to encourage the immune system to be a little more sensitive in order to recognize and eliminate diseases."

Lillemeier's team is working to identify new principles that determine if T cells respond to a threat versus staying quiet. In addition, they are testing whether their findings could be applied across additional processes in T cells and other immune cells. Because proteins have many of the same modular building blocks, in principle, any protein with structural characteristics comparable to those of ZAP-70 could be controlled by similar mechanisms, Lillemeier says.