In a new study, researchers have found cellular mechanisms responsible for eliminating T cells that pose autoimmune dangers.
Scientists at the Georgia Institute of Technology reported that in the newly discovered mechanisms, aggressively developing thymocytes are made to commit suicide to prevent them from causing damage to the body, while maintaining the normally developing thymocytes that grow into T cells and act against infections as well as cancer.
Although the mechanisms are interlinked with biochemical processes, they also function mechanically tugging, grasping, and clumping, according to the study authors. Findings of the study were published in the journal Nature Immunology.
Usually, scientists pursue such mechanisms through chemical reactions, but in the new study physical experiments were used that make uncommon discoveries about the effects of forces between key proteins in the living cells.
Cheng Zhu, who led the study explained that previous experiments involving chemical reactions in vitro where protein are not considered, miss the dynamic force. In the new study, force is taken as an important factor in thymocyte selection. Thymocytes are the cells made in the bone marrow and transferred to the thymus where they are exposed to a series of selection tests, causing them to kill themselves if any one test is failed. On the other hand, passing all the tests promotes tymocytes into T cells that protect the body.
One selection monitors T cells receptors (TCRs) present on the thymocyte membrane, ensuring they are properly formed and observing their ability to recognize self-antigens, molecules that identify cells of the body. Another selection called ‘negative selection’ check that TCRs do not response aggressively to self-antigens. Together, these two selections reveal that thymocytes have TCRs that tolerate self- but react to enemy antigens.
In the negative selection, other cells extends self-antigens on their membrane to interact with the TCRs of thymocytes; these interactions determine whether thymocytes advance or die. Analyzing the forces involved in such interactions uncover a new signaling loop and mechanical properties equivalent to two-handed grip and tug by the cells. The first hand of the grip would be the TCRs and self-antigen would be the second hand, presenting in manner like someone else’s hand is holding out a ball to the first hand.
If the first hand reacts aggressively to the self-antigen, an assistant hand within TCR called CD8 coming from the side acts as a lever, which connects to important mechanism within the cells and is considered a part of the TCR site. According to the researchers, the two-handed mechanism remarkably resisted the force applied to separate the grip between the TCR and self-antigen, extending the duration of the interaction. A long grip led to signals encouraging self-destruction of the thymocyte.
Improving the understanding of selection mechanisms that stop immune cells causing dangers to human tissue, while fighting infections and cancer, could someday lead to novel immune-regulating therapies, the researchers said.