When the immune system overreacts and begins attacking the body, the only option may be to suppress the entire system, potentially risking infections or cancer.

Scientists at UC San Francisco have discovered a more precise method to regulate the immune system.

The technology uses engineered T cells that act as immune “referees” to soothe overreacting immune responses. They also can mop up inflammatory molecules. 

The new approach could prevent the body from rejecting transplanted organs and tissues, such as pancreatic islet cells, sometimes used to treat type 1 diabetes. Thus, recipients would not need to take harsh immunosuppressant drugs.

“This technology has the potential to restore balance to the immune system,” said Wendell Lim, PhD, a cellular and molecular pharmacology professor at UCSF and co-senior author of the paper published on December 5 in *Science*. “We view it as a potential platform for addressing various types of immune dysfunction.”

Lim and his colleagues were inspired by “suppressor” cells, the immune system’s natural brakes. They wanted to use suppressor cells to temper immune responses, such as inflammation.

Unfortunately, suppressor cells can’t always stop a dangerous immune response. In type 1 diabetes, for example, the immune system destroys pancreatic islet cells while these suppressor cells stand by. 

The team adapted the suppressor cells’ anti-inflammatory abilities to work in CD4 immune cells, the same cells that are used to make cancer-killing CAR T cells. They also gave these cells a molecular sensor to guide them to their target tissue in the body.

Proof of principle in type 1 diabetes 

The scientists tailored a batch of immune referees to search for human pancreatic islet cells and then produce TGF-Beta and CD25, molecules that can muzzle killer T cells.

They introduced the engineered referee cells into mice that had received a transplant of human islet cells, modelling the treatment for type 1 diabetes.

The referee cells found the vulnerable islet cells and stopped the killer T cells from attacking, and the islet cells survived.

“It would be life-changing for people with type 1 diabetes if they could get new islet cells without needing to take immunosuppressants and stop having to take insulin every day,” said Audrey Parent, PhD, associate professor in the UCSF Diabetes Center and a co-senior author of the paper.

Lim envisions a future in which organ transplant patients, or those with autoimmune diseases, receive therapies that only treat the specific regions of the body where the immune system is misbehaving. 

This could prevent the significant side effects from general immunosuppressants and the infections and cancers that arise when the immune system is disabled completely.

The new technology could also be used to fine-tune CAR T cell therapies for cancer so that these cells only attack tumors and not healthy tissue.