Mechanical Forces in Immunological Synapse Measured

Although T cells play a central role in our immune system by detecting invaders and then triggering an immune reaction, the molecular, biophysical, and cellular mechanisms underlying this process are not well understood. For a study published in Nature Communications today, a team devised a method to measure the mechanical forces involved when an antigen is recognized.

When viruses attack our body, infected cells present various fragments of viral proteins on their surface. T cells examine such cells for the presence of such antigens. "This works according to the lock-and-key principle," explains Johannes Huppa , co-senior author on the paper. "For each antigen, the body must produce T cells with matching T cell receptors (TCRs). Put simply, each T cell recognizes only one specific antigen to then subsequently trigger an immune response."

That particular antigen, or more precisely, any antigenic protein fragment presented that exactly matches the T cell's TCR, can form a somewhat stable bond. The question that needs to be answered by the T cell is: how stable is the binding between antigen and receptor?

"Let's say we wish to find out whether a surface is sticky—we then test how stable the bond is between the surface and our finger," says co-senior author Gerhard Schütz. "We touch the surface and pull the finger away until it comes off. That's a good strategy because this pull-away behavior quickly and easily provides us information about the attractive force between the finger and the surface."

In principle, T cells do exactly the same. T cells are not static, they deform continuously and their cell membrane is in constant motion. When a TCR binds to an antigen, the cell exerts a steadily increasing pulling force until the binding eventually breaks. This can provide information about whether it is the antigen that the cell is looking for.

"This process can actually be measured, even at the level of individual molecules," explains first author Janett Göhring. "A special protein was used for this, which behaves almost like a perfect nano-spring, explain the two other first authors Florian Kellner and Dr. Lukas Schrangl. "The more traction is exerted on the protein, the longer it becomes. With special fluorescent marker molecules, you can measure how much the length of the protein has changed, and that provides information about the forces that occur." In this way, the group was able to show that T cells typically exert a force of up to 5 pico-newtons—a tiny force that can nevertheless separate the receptor from the antigen.