A team of researchers has made steps towards better understanding how T cells function – by using their antigen like receptors like sticky fingers.
T cells are a critical component of the immune system – using T cell receptors (TCR) to recognise dangerous invaders or cancer cells, triggering an immune reaction. However, our understanding of this recognition process at a molecular level is not clearly understood.
Now, in a joint project funded by the Vienna Science and Technology Fund and the FWF, a team of immunologists, biochemists, and biophysicists from TU Wien and MedUni have investigated which mechanical processes take place when an antigen is recognised.
The findings have been published in Nature Communications.
When viruses attack
When viruses attack the body, infected cells present various fragments of viral proteins on their surface which T cells then examine for the presence of antigens. Johannes Huppa, biochemist and immunology professor at MedUni Vienna, said: “This works according to the lock-and-key principle. For each antigen, the body must produce T cells with matching TCRs. Put simply, each T cell recognises only one specific antigen to then subsequently trigger an immune response.”
The team found that as T cells move, their TCRs pull on the antigen with a tiny force – about five pico-newtons, which is sufficient to break the bonds between the TCRs and the antigen. This also helps T cells to find out whether they are interacting indeed with the antigen they are looking for.
“Each T cell recognises one specific antigen particularly well,” added Huppa. “To do so, it features around 100,000 TCRs of the same kind on its surface.”
That antigen, or any antigenic protein fragment presented that exactly matches the T cell’s TCR, can form a somewhat stable bond and the T cell needs to find out how stable the binding is between antigen and receptor.
Gerhard Schütz, Professor of Biophysics at TU Wien, pointed out that the process is much akin to finding out whether a surface is sticky.
“We then test how stable the bond is between the surface and our finger,” he said. “We touch the surface and pull the finger away until it comes off. That’s a good strategy because this pull-away behaviour quickly and easily provides us information about the attractive force between the finger and the surface.”
T cells 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 – which 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,” says Dr Janett Göhring, who was active as co-ordinator and first author of the study at both MedUni Vienna and TU Vienna.
Two other first authors Florian Kellner and Dr Lukas Schrangl from MedUni Vienna and TU Vienna respectively, added that: “A special protein was used for this, which behaves almost like a perfect nano-spring. 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.”
Using this method, the group was able to show that T cells typically exert a force of up to five pico-newtons – a tiny force that can separate the receptor from the antigen.
“Understanding the behaviour of T cells at the molecular level would be a huge leap forward for medicine. We are still leagues away from that goal,” says Huppa.
Schütz added: “But we were able to show that not only chemical but also mechanical effects play a role. They have to be considered together.”