A new mRNA-based approach turns the liver into an immune booster, helping aging bodies fight disease as if they were younger again.
As the immune system weakens with age, scientists have found a way to restore some of its lost strength. By delivering mRNA to the liver, they created a temporary source of immune-boosting signals that normally come from the thymus. Older mice treated this way produced more effective T cells and responded far better to vaccines and cancer treatments. The strategy could one day help extend healthy years of life.
As people age, their immune system often becomes less effective. Populations of T cells shrink, and the remaining cells may respond more slowly to germs. That slowdown can leave older adults more vulnerable to various infections.
To address this age-related decline, scientists from MIT and the Broad Institute developed a method to temporarily reprogram liver cells to enhance T cell performance. The goal is to make up for the reduced output of the thymus, the organ where T cells normally mature.
In the study, the team used mRNA to deliver three important factors that support T cell survival. With this approach, they rejuvenated the immune systems of mice. Older mice that received the treatment produced larger, more diverse T cell populations after vaccination and showed improved responses 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 essential like the immune system, hopefully we can help people stay free of disease for a longer span of their life,” says Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT, who has joint appointments in the departments of Brain and Cognitive Sciences and Biological Engineering.
Zhang is also an investigator at the McGovern Institute for Brain Research at MIT, a core institute member at the Broad Institute of MIT and Harvard, and an investigator in the Howard Hughes Medical Institute. He is the senior author of the new study. Former MIT postdoc Mirco Friedrich is the lead author of the paper, which was published in Nature.
The Thymus and Why T Cells Decline With Age
The thymus is a small organ located in front of the heart and is essential for developing a healthy supply of T cells. Inside the thymus, immature T cells undergo a checkpoint process that helps generate a diverse set of T cells. The thymus also releases cytokines and growth factors that help T cells survive.
But beginning in early adulthood, the thymus starts to shrink. This process, called thymic involution, reduces the body’s ability to produce new T cells. By about age 75, the thymus is essentially nonfunctional.
“As we get older, the immune system begins to decline. We wanted to think about how we can maintain this kind of immune protection for a longer period of time, and that’s what led us to think about what we can do to boost immunity,” Friedrich says.
Earlier efforts to rejuvenate the immune system have often focused on delivering T cell growth factors into the bloodstream, but this approach can cause 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 chose a different strategy. They asked whether the body could be prompted to create a temporary “factory” that produces the same T cell-stimulating signals as the thymus.
“Our approach is more of a synthetic approach,” Zhang says. “We’re engineering the body to mimic thymic factor secretion.”
They selected the liver for the job for several reasons. The liver can produce large amounts of protein even in old age. It is also easier to deliver mRNA to the liver than to many other organs. In addition, all circulating blood flows through the liver, including T cells, making it a practical place to release immune-supporting signals into the bloodstream.
To build this factory, the researchers picked three immune cues involved in T cell maturation. They encoded these factors into mRNA and packaged the sequences into lipid nanoparticles. After injection into the bloodstream, the nanoparticles are taken up by the liver. Hepatocytes take up the mRNA and begin translating the encoded proteins.
The three factors delivered were DLL1, FLT-3, and IL-7. These signals help immature progenitor T cells develop into fully differentiated T cells.
Vaccine and Cancer Immunotherapy Benefits in Older Mice
Experiments in mice showed multiple positive outcomes. In one test, the researchers injected the mRNA particles into 18-month-old mice, roughly comparable to humans in their 50s. Because mRNA does not last long in the body, the team gave repeated doses over four weeks to keep the liver producing the factors consistently.
After the treatment, T cell populations increased substantially in both size and function.
The team then examined whether the approach improved vaccine responses. They vaccinated mice with ovalbumen, a protein found in egg whites that is often used to study immune reactions to a specific antigen. In 18-month-old mice that received the mRNA treatment before vaccination, the number of cytotoxic T cells targeting ovalbumen doubled compared with untreated mice of the same age.
The researchers also found that the mRNA method could strengthen responses to cancer immunotherapy. They treated 18-month-old mice with the mRNA, implanted tumors, and then administered a checkpoint inhibitor. This drug targets PD-L1 and is intended to release the brakes on the immune system, allowing T cells to attack tumor cells more effectively.
Mice that received both the checkpoint inhibitor and the mRNA treatment had much higher survival rates and lived longer than mice that received the checkpoint inhibitor drug without the mRNA treatment.
The researchers determined that all three factors were required for the immune improvement. 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 might further strengthen immune function. They also want to investigate how the treatment influences other immune cells, including B cells.
Other authors of the paper include Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, and Rhiannon Macrae.