As people age, their immune system function declines. T cell populations become smaller and can’t react to pathogens as quickly, making individuals more susceptible to a variety of infections. To try to overcome this decline, researchers at MIT have found a way to temporarily program cells in the liver to improve T cell function. The team’s study suggested that reprogramming can compensate for the age-related decline of the thymus, where T cell maturation normally occurs.
By delivering to liver cells mRNAs encoding DLL1, FLT3L, and IL-7—three key factors that usually promote T cell survival—the researchers were able to rejuvenate the immune systems of mice. Aged animals that received the treatment showed much larger and more diverse T cell populations in response to vaccination, and they also responded better to cancer immunotherapy treatments. The researchers suggest that if their approach could be developed for use in patients, it could help individuals lead healthier lives 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,” said Feng Zhang, PhD, 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, who 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, is senior author of the team’s published paper in Nature, titled “Transient hepatic reconstitution of trophic factors enhances aged immunity.” First author is former MIT postdoc Mirco Friedrich, PhD. In their paper, the team wrote, “In summary, this study demonstrates that transiently repurposing the liver to express and secrete various therapeutic proteins could be a generalizable approach to engineering physiological processes.”
“Aging erodes human immunity, in part by reshaping the T cell repertoire, leading to increased vulnerability to infection, malignancy, and vaccine failure,” the authors wrote. Central to this T cell repertoire decline is shrinkage of the thymus. This small organ, located in front of the heart, plays a critical role in T cell development.
Within the thymus, immature T cells go through a checkpoint process that ensures a diverse repertoire of T cells. The thymus also secretes cytokines and growth factors that help T cells to survive. However, starting in early adulthood, the thymus begins to shrink. This process, known as thymic involution, leads to a decline in the production of new T cells. By the age of approximately 75 years, the thymus is essentially nonfunctional.
“As we get older, the immune system begins to decline. We wanted to think about how can we 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.
Previous work on rejuvenating the immune system has focused on delivering T cell growth factors into the bloodstream, but that can have harmful side effects. Researchers are also exploring the possibility of using transplanted stem cells to help regrow functional tissue in the thymus. “Although these strategies have provided valuable insights into immune aging, they have been limited by effect size, toxicity, or clinical feasibility,” the investigators further noted.
The MIT team took a different approach: They wanted to see if they could create a temporary “factory” in the body that would generate the T-cell-stimulating signals that are normally produced by the thymus. “Our approach is more of a synthetic approach,” Zhang explained. “We’re engineering the body to mimic thymic factor secretion.”
The researchers selected the liver as their factory location. The liver has a high capacity for producing proteins, even in old age. It is, in addition, easier to deliver mRNA to the liver than to most other organs of the body. The liver also presented as a promising target because all of the body’s circulating blood has to flow through the organ, and this includes T cells.
To create their factory, the researchers identified three immune pathways that are important for T cell maturation. “We first identified signalling pathways in the thymus and peripheral blood T cells that decline with age,” they wrote. The team then encoded these three factors in mRNA sequences that could be delivered by lipid nanoparticles. “We then delivered mRNAs encoding these factors (DLL1, FLT3-L, and IL-7) to the liver using lipid nanoparticles (LNPs).”
The team showed that when injected into the bloodstream, these particles accumulate in the liver and the mRNA is taken up by hepatocytes, which begin to manufacture the proteins encoded by the mRNA.
In vivo tests in mice revealed a variety of beneficial effects of the treatment. First, the researchers injected the mRNA particles into mice that were 18-months of age, equivalent to humans in their 50s. Because mRNA is short-lived, the researchers gave the mice multiple injections over four weeks to maintain a steady production by the liver. They found that following treatment, T cell populations showed significant increases in size and function.
The researchers then tested whether the treatment could enhance the animals’ response to vaccination. They vaccinated the mice with ovalbumin, a protein found in egg whites that is commonly used to study how the immune system responds to a specific antigen. The team found that in 18-month-old mice that received the mRNA treatment before vaccination, the population of cytotoxic T cells specific to ovalbumin doubled, compared with the responses of mice of the same age that did not receive the mRNA treatment.
The study, in addition, showed that mRNA treatment can boost the immune system’s response to cancer immunotherapy. The investigators delivered the mRNA treatment to 18-month-old mice that then received tumor implants and were treated with a checkpoint inhibitor drug. This drug, which targets the protein PD-L1, is designed to help take the brakes off the immune system and stimulate T cells to attack tumor cells.
“Alongside recent work with mRNA-encoded cytokines, these data highlight liver-encoded delivery of immune modulators as a strategy to mitigate age-related immune dysfunction and overcome components of immunotherapy resistance,” the researchers reported.
The results showed that mice receiving the mRNA treatment demonstrated much higher survival rates and longer lifespans than animals that received the checkpoint inhibitor drug but no mRNA treatment.
The investigators found that all three factors were necessary to induce this immune enhancement; none could achieve all aspects of it on their own. They now plan to study the treatment in other animal models and to identify additional signaling factors that may further enhance immune system function.
The team also hopes to study how the treatment affects other immune cells, including B cells. “Our results show that delivery to the liver of mRNA encoding DLL1, IL-7, and FLT3-L in combination successfully enhanced immune function in aged mice,” they stated. “These findings underscore the promise of mRNA-based strategies for systemic immune modulation and highlight the potential of interventions aimed at preserving immune resilience in ageing populations.”
