Engineered Immune Cells Act As “Referees” To Soothe Inflammation

When the immune system overreacts and starts attacking the body, the only option may be to shut the entire system down and risk developing infections or cancer.

But now, scientists at UC San Francisco may have found a more precise way to dial the immune system down.

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 be used to stop the body from rejecting transplanted organs and tissues, such as pancreatic islet cells, which are sometimes used to treat type 1 diabetes. That way, recipients would not need to take harsh immunosuppressant drugs.

“This technology can put the immune system back into balance,” said Wendell Lim, PhD, UCSF professor of cellular and molecular pharmacology and co-senior author of the paper, which appears Dec. 5 in Science. “We see it as a potential platform for tackling all kinds of immune dysfunction."

Lim and his colleagues were inspired by “suppressor” cells, which are the immune system’s natural brakes. They wanted to take advantage of these suppressor cells’ power 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 just stand by.

The team adapted the suppressor cells’ anti-inflammatory abilities to work in CD4 immune cells. These are 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, modeling 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 as well as the infections and cancers that arise when the immune system is disabled completely.

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

“This puts so many more options on the table for dealing with some of the biggest challenges in medicine,” said Lim, who directs the UCSF Cell Design Institute. “We hope this can benefit patients in the not-so-distant future.”

Reference: Reddy NR, Maachi H, Xiao Y, et al. Engineering synthetic suppressor T cells that execute locally targeted immunoprotective programs. Science. 2024;386(6726):eadl4793. doi: 10.1126/science.adl4793

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