Counterintelligence immunity
How the Immune System Detects Hidden Intruders
Anna Yudina, "Scientific Russia"
Research by Texas A&M College of Engineering may lead to new approaches to the treatment of viruses and cancer," says a press release of Discoveries Made In How Immune System Detects Hidden Intruders.
Research led by Dr. Wonmuk Hwang has led to a better understanding of how components of the body's immune system find invaded or damaged cells, which may lead to new approaches to the treatment of viruses and cancer.
Wonmuk Hwang, associate professor of biomedical Engineering at Texas A&M University, wrote about this in an article recently published in the journal Proceedings of the National Academy of Sciences (Wonmuk Hwang et al., The αßTCR mechanosensor exploits dynamic ectodomain allostery to optimize its ligand recognition site).
When viruses enter the body, the immune system begins to search for and destroy the attacker. T cells are one of the components of the immune system, and they look for viruses hiding in host cells, acting as the main line of defense against antigens or foreign bodies. T cells examine the surface of other cells by studying materials collected from inside the cell and represented by molecules of the main histocompatibility complex (MHC) on the cell surface.
"The problem is that there are hundreds of thousands of MHC molecules displaying peptides, and only a few of them belong to invading cells, if they appear at all," Hwang said. "The rest of the molecules are normal products of cellular metabolism, which means that T-lymphocytes have to look for a needle in a haystack."
Recently, researchers have discovered that T cells increase their detection ability mechanically: when T cells examine the surface of other cells, a natural contact force is created. If a cell is infected with an antigen, the applied force leads to a "chain link" between T cell receptors (TCR) and MHC molecules, which enhances contact. This connection does not occur between TCR and MCH molecules that do not carry specific antigens.
The T-cell receptor and the main histocompatibility complex represent a yellow-colored antigen.
However, it is almost impossible to see this interaction experimentally with atomic accuracy, so Hwang developed a computer simulation that could realistically demonstrate and analyze the interaction between TCR and MHC molecules when force is applied.
"Only simulation can see and analyze the movement of molecules under load. The laboratory experiment does not have such permission," Hwang said. "Experimentally determined atomic structures of proteins are static images, but when a molecule moves, you have almost no way to see the movement."
Hwang discovered how the movement between the TCR parts controls their interaction with MHC molecules. When force is applied, the movement is suppressed only when the MHC molecule has the corresponding antigen, thereby stabilizing the entire complex. In other cases, blocking with TCR will be denied, and constant movement between them will eventually lead to their disconnection. This is similar to the "lock and key" system, in which the lock and key constantly change shape, and only with a perfect match and with the appropriate level of force, the molecules can lock together.
Hwang said knowing which parts of the molecule respond to the force can help adapt T cells to specific applications. In addition to fighting infections, TCR are also rising stars in cancer therapy.
"If you teach T-lymphocytes to see these cancer antigens, it will be a really specific therapy," Hwang said. – Chemotherapy kills all cells. But T cells can be trained to recognize cancer cells with exceptional accuracy."
Hwang said the next step for him will be to study what is common and what relates to specific T cell receptor systems.
"To see how this principle applies to different T-cell receptors, I'm going to expand on this initial discovery," Hwang said. "This is the first work in which the functioning mechanism of T-cell receptors was discovered."
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