Researchers have engineered antibody-like T cell receptors (TCRs) that can specifically stick to cells infected with cytomegalovirus (CMV), a virus that causes lifelong infection in more than half of adults by age 40.
In the healthy immune system, CMV lies dormant as T cells circulate through the body and detect infected cells. While antibodies recognize only proteins at the cell surface, T cells use their membrane-bound TCRs to detect disease-associated proteins hiding inside the cellular membrane. The T cells can then destroy the infected cell. However, for immunocompromised patients, this defensive mechanism is diminished and CMV infection can become life-threatening.
Researchers have used T cells to treat disease before, but engineering and transplanting whole T cells is both costly and invasive. In a new study published today in the Journal of Biological Chemistry, a team of engineers took an alternative approach, producing CMV-detecting TCRs that, like antibodies, float freely through the body and bind tightly to their diseased targets.
“Right now we’ve got a molecule that looks like an antibody but it binds to a [CMV-associated] peptide that would normally be recognized by a TCR,” says senior author Jennifer Maynard of the University of Texas at Austin. “Antibodies cannot normally access these molecules so that’s a big deal.”
To strengthen their TCRs’ bonds with their targets, the authors randomly mutated the DNA of the TCR component that detects the CMV peptide. They then inserted many versions of the mutated DNA into hamster cells, which manufactured about a million different types of TCR.
“We found one that was our favorite,” Maynard says. “We improved the binding affinity 50-fold.”
According to Maynard, this “antibody-like” TCR strategy could be used to track disease progression in patients, evaluate how well developing vaccines are working, restore the immune response in immunocompromised patients, and even treat glioblastoma.
“Our protein could be used to specifically target glioblastoma cells, and it would provide a very unique marker,” Maynard says. “We would use this to monitor or kill some of those tumor cells.”
Image: T cells are adept at killing cytomegalovirus (CMV)-infected cells by virtue of a T cell receptor (TCR) that recognizes intracellular CMV-associated proteins that become presented on the cell surface. By contrast, antibodies float freely through the body, binding tightly to secreted and membrane proteins and tagging them for recognition by other immune cells. This work combined the cell targeting properties of a TCR and the tight binding of an antibody with other modifications to create a new molecule able to detect and tag CMV-infected cells. This hybrid protein represents a new strategy to identify and possibly eliminate CMV-infected cells. Image courtesy of Jennifer Maynard/Ellen Wagner/University of Texas.