A paper published today in the Proceedings of the National Academy of Sciences is being heralded as a leap toward developing killer T cells to attack tumors.
When T cells are cultured in the lab, they sit around at equilibrium, waiting to bump into cancerous cells. However, inside the body they much more actively seek out infected cells. A team of scientists from Vanderbilt University and collaborators at Harvard University investigated this phenomenon and reported that in this active mode, they found cells showing much less evidence of cancer than previously thought.
According to Matt Lang, Vanderbilt University professor of chemical and biomolecular engineering, the research promises to change what immunologists are looking for, because it demonstrates that T cells can trigger killing of cells with far less evidence of infectious pathogens, physical damage and malignant transformations than previously believed. Now, researchers will look for T cells that demonstrate potential for the strongest binding when they're flung at damaged cells.
In their research, Lang and Ph.D. student Yinnian Feng used highly focused laser beams to help characterize the T cells' structure and perform single-molecule analyses. These “optical tweezers” were used to pick up microscopic spheres and coat them with the same peptides as found on diseased cells. They would then place the spheres onto T cells. Then 10 piconewtons of force was applied to the T cell. A special dye applied to the T cell immediately revealed an increase of intracellular calcium, which shows that it is activated. Then Feng and Lang began removing a peptide at a time as their experiments progressed and learned that, with this tiny amount of force, the T cell can do its job when contacting as few as two peptides.
"With the very precise microscopes we have, we didn't see repetitive binding. We saw a single binding event," Lang said. "This paper is telling us about mechanism, about how the system actually works. It's basically saying that we're dealing with a mechanosensor that requires force to be activated. Strategically, it's changing what we should be looking for."
"We can, for the first time, pick the closer on the baseball team who can reliably pitch fastballs," Lang said. "Which T cell do you pick, which one do you put back into the patient to fight their disease? Maybe you get lucky and pick the right one. With these new tests, we can measure the interaction under the native, energized state. We've found the sweet spot for reliably triggering them."
Caption: A trapped bead (right) decorated with a foreign antigen is actively placed on a T cell (left) and force is applied to facilitate recognition by the T cell receptor complex.