Scientists Find a Way to Rejuvenate the Immune System in Old Age

With age, the immune system often becomes less effective. The number of T cells decreases, and the remaining cells may respond more slowly to germs. This slowdown can make older adults more susceptible to many types of infections. To counteract this age-related decline, scientists at MIT and the Broad Institute have developed a method to temporarily reprogram liver cells to boost the performance of T cells. The goal is to compensate for the reduced performance of the thymus, the organ where T cells normally mature.

Restoring the Immune System

In the study, the team used mRNA to deliver three key factors that support T-cell survival. Using this approach, they were able to rejuvenate the immune systems of mice. Older mice that received the treatment produced larger and more diverse T-cell populations after vaccination and also showed an improved response to cancer immunotherapy. The researchers say that if this strategy can be adapted for patients, it could help people stay healthier as they age.

“If we can restore something as essential as the immune system, we can hopefully help people stay disease-free longer in their lives,” says Feng Zhang, James and Patricia Poitras Professor of Neuroscience at MIT, who is affiliated with both the Department of Brain and Cognitive Sciences and the Department of Biological Engineering. Zhang is also a researcher at the McGovern Institute for Brain Research at MIT, a core member of the Broad Institute of MIT and Harvard, and a researcher at the Howard Hughes Medical Institute. He is the senior author of the new study. Former MIT postdoctoral fellow Mirco Friedrich is the lead author of the study, which was published in Nature.

The Rhymus and Why T cells Decline With Age

The thymus is a small organ located in front of the heart that is essential for building a healthy supply of T cells. Inside the thymus, immature T cells undergo a screening process that helps create a diverse group of T cells. The thymus also releases cytokines and growth factors that support the survival of T cells.

But from early adulthood onwards, the thymus begins to shrink. This process is called thymic involution and reduces the body’s ability to produce new T cells. By the age of about 75, the thymus is essentially non-functional. “As we age, the immune system begins to decline. We wanted to think about how we could maintain this type of immune protection over a longer period of time, and that led us to think about what we could do to strengthen immunity,” says Friedrich.

Previous efforts to rejuvenate the immune system have often focused on delivering T-cell growth factors via the bloodstream, but this approach can have harmful side effects. Other researchers are investigating whether transplanted stem cells could help regrow functional thymus tissue.

A Temporary Liver Factory Powered by mRNA

The MIT team opted for a different strategy. They wondered whether the body could be stimulated to create a temporary “factory” that produces the same T-cell-stimulating signals normally produced by the thymus. “Our approach is more of a synthetic approach,” Zhang explains. “We manipulate the body to mimic the secretion of thymus factors.”

They chose the liver for this task for several reasons. The liver can still produce large amounts of protein even in old age. It is also easier to transport mRNA to the liver than to many other organs. Furthermore, all circulating blood flows through the liver, including T cells, making it a convenient location to deliver immune-supporting signals into the bloodstream.

To build this factory, the researchers selected three immune signals involved in T cell maturation. They encoded these factors in mRNA and packaged the sequences into lipid nanoparticles. After injection into the bloodstream, the nanoparticles accumulate in the liver. Hepatocytes take up the mRNA and begin producing the proteins encoded within it. The three factors administered were DLL1, FLT-3, and IL-7. These signals help immature precursor T cells develop into fully differentiated T cells.

Benefits of Vaccines and Cancer Immunotherapy in Older Mice

Experiments in mice showed several positive results. In one test, the researchers injected the mRNA particles into 18-month-old mice, which are roughly comparable to humans in their fifties. Since mRNA does not last long in the body, the team administered repeated doses over four weeks to get the liver to continuously produce the factors. After treatment, both the size and function of the T cell populations increased significantly.

The team then investigated whether this approach improved vaccine responses. They vaccinated mice with ovalbumin, a protein found in egg whites that is often used to study immune responses to a specific antigen. In 18-month-old mice that received mRNA treatment prior to vaccination, the number of cytotoxic T cells directed against ovalbumin doubled compared to untreated mice of the same age. The researchers also found that the mRNA method can enhance the response to cancer immunotherapy. They treated 18-month-old mice with mRNA, implanted tumors in them, and then administered a checkpoint inhibitor drug. This drug targets PD-L1 and is designed to release the brakes on the immune system so that T cells can attack tumor cells more effectively.

Mice that received both the checkpoint inhibitor and mRNA treatment had much higher survival rates and lived longer than mice that received the checkpoint inhibitor drug without the mRNA treatment. The researchers found that all three factors were necessary for the improvement in the immune system. No single factor could reproduce the full effect. Next, the team plans to test the approach in additional animal models and search for other signaling factors that could further enhance immune function. They also want to investigate how the treatment affects other immune cells, including B cells.