In order to detect pathogens or cancer cells, the body police apparently use their antigen receptors like sticky fingers: Through ingenious experiments, researchers have recorded the tiny tensile force that probably serves as an indication during the search. In the case of the binding between the receptor of a T cell and the matching antigen, a tensile force of around five pico newtons is therefore necessary for separation. When the T cell perceives this stickiness, it initiates immune responses, according to the explanatory model.
Without the forces of order, all hell would break loose in our body: Pathogens and cancer cells have to be constantly kept in check by the immune system, otherwise there is a risk of illness and death. T cells play a central role in this: with the help of so-called T cell receptors on their surface, they can recognize dangerous intruders as well as degenerate or infected cells in the body, whereupon they trigger immune reactions that lead to elimination. It is generally known that they recognize the “bad guys” by special surface features: so-called antigens trigger the reaction.
“Every T cell can recognize a certain antigen particularly well. To do this, it has around 100,000 similar T cell receptors on its surface, ”explains Johannes Huppa from the Medical University of Vienna. The detection of the antigens is based on the lock and key principle: “For each antigen, the body must produce T cells with suitable T cell receptors. Put simply, each T cell only recognizes one specific antigen and then triggers an immune reaction, ”says Huppa. However, there are still many unanswered questions about which molecular processes underlie the recognition process. It is assumed that not only biochemical but also mechanical processes play a role. Presumably, the strength of the bond between the antigen and the T cell receptor serves as an additional source of information.
Spider silk protein as a measuring instrument
But how strong could this bond strength be? Huppa and his colleagues have now investigated this question experimentally. “You can actually measure the process, and that at the level of individual molecules,” says first author Janett Göhring from the Vienna University of Technology. She and her colleagues used a protein made from spider silk, which behaves almost like a perfect nano-feather: the more tensile force is exerted, the longer the protein becomes and is therefore suitable as a measuring instrument. During the experiments, the researchers combined a pad with an antigen using this nano-feather. The researchers allowed T cells to bind to the corresponding receptor.
With the help of fluorescent marker molecules, they then determined how much the length of the protein changed when the T cell detached again and the connection was broken. In this way, the team was able to draw conclusions about the forces involved: According to this, up to five pico-newtons are required to separate the receptor and antigen. For comparison: you would have to pull on more than 100 million such feathers at the same time to be able to perceive stickiness with your finger. But at the molecular level, the T cells’ perception can be based on a principle similar to how we use our fingers to determine the stickiness of an object, the scientists say.
Like fingers on a sticky surface
“Humans register how stable the bond between the surface and our finger is: We touch the surface and pull the finger away until it comes loose,” says co-author Gerhard Schütz from the Vienna University of Technology. “The tear-off behavior can quickly and easily provide us with information about the attractive force between the finger and the surface.” In principle, the T-cell probably does the same thing: It is not static – its cell membrane is constantly deforming, which corresponds to our finger movements. When a T-cell receptor binds to an antigen, the cell exerts a steadily increasing tensile force until the bond finally breaks again. The results show that around five pico-Newtons could convey that the antigen is actually the right one.
“A better understanding of the behavior of T cells at the molecular level would be a huge leap forward for medicine. We are still a long way from that, ”says Huppa. “But”, adds his colleague Schütz, “we were able to make it clear that not only chemical but also mechanical effects can play a role. The combination makes a lot of sense, ”says the scientist.
Source: Vienna University of Technology, specialist article: Nature Communications, doi: 10.1038 / s41467-021-22775-z