As people age, immune function steadily declines. In particular, T-cell populations shrink and respond more slowly to pathogens, leaving older adults more vulnerable to infections and disease.
To address this challenge, researchers at the Massachusetts Institute of Technology (MIT) have developed a novel approach to temporarily reprogram liver cells to enhance T-cell function. By doing so, they were able to compensate for the age-related decline of the thymus—the organ where T cells normally mature.
mRNA-Based Approach Restores T-Cell Function
Using mRNA technology to deliver three critical immune-supporting factors, the researchers successfully rejuvenated the immune systems of ageing mice. Notably, treated mice developed larger and more diverse T-cell populations following vaccination and showed improved responses to cancer immunotherapy.
If adapted for human use, this approach could help people maintain stronger immune protection as they age. According to senior author Feng Zhang, restoring essential systems such as immunity may help individuals remain healthier and disease-free for longer periods of life.
Role of the Thymus in Immune Decline
The thymus, a small organ located near the heart, plays a vital role in T-cell development. Within the thymus, immature T cells undergo a selection process that ensures diversity and functionality. In addition, the thymus releases cytokines and growth factors that support T-cell survival.
However, thymic involution begins in early adulthood. As the thymus gradually shrinks, the body produces fewer new T cells. By around the age of 75, the thymus becomes largely nonfunctional, contributing significantly to immune ageing.
A Synthetic Alternative to Thymic Function
While earlier efforts to rejuvenate immunity focused on injecting growth factors or transplanting stem cells, these approaches can carry risks or technical challenges. Instead, the MIT team pursued a synthetic strategy.
Rather than attempting to repair the thymus itself, the researchers aimed to create a temporary internal “factory” that could produce thymus-like signals elsewhere in the body. This approach, Zhang explained, allows the body to mimic thymic factor secretion without invasive intervention.
Why the Liver Became the Target
The team selected the liver as the site for this temporary immune factory for several reasons. Importantly, the liver maintains strong protein-production capacity even in old age. Moreover, researchers can deliver mRNA to the liver more efficiently than to most other organs. Finally, since all circulating blood—including T cells—passes through the liver, it provides an ideal platform for immune modulation.
Key Immune Signals Encoded in mRNA
To build the system, the researchers identified three immune signals essential for T-cell maturation: DLL1, FLT-3 and IL-7. They encoded these factors into mRNA molecules and delivered them using lipid nanoparticles.
Once injected into the bloodstream, the nanoparticles accumulated in the liver. Hepatocytes then absorbed the mRNA and began producing the encoded proteins, which supported the maturation and survival of progenitor T cells.
Enhanced Immunity Demonstrated in Ageing Mice
In initial experiments, the researchers treated 18-month-old mice—roughly equivalent to humans in their 50s—with repeated mRNA injections over four weeks. Because mRNA degrades quickly, multiple doses were necessary to sustain protein production.
Following treatment, the mice showed significant increases in both the size and functionality of their T-cell populations.
Stronger Vaccine Responses Observed
To test vaccine responsiveness, the researchers immunised the mice with ovalbumin, a standard model antigen. In treated mice, the number of cytotoxic T cells specific to ovalbumin doubled compared to untreated mice of the same age. This result demonstrated that the mRNA therapy substantially enhanced immune responsiveness.
Improved Outcomes in Cancer Immunotherapy
As reported by medicalxpress, the team also evaluated whether the treatment could improve responses to cancer immunotherapy. They treated aged mice with the mRNA therapy before implanting tumours and administering a checkpoint inhibitor that blocks PD-L1.
Mice that received both the mRNA treatment and the checkpoint inhibitor survived significantly longer and showed higher survival rates than mice that received immunotherapy alone. These findings suggest that immune rejuvenation can amplify the effectiveness of cancer treatments.
All Three Factors Prove Essential
Importantly, the researchers found that all three immune factors were necessary to achieve full immune enhancement. None of the individual components could produce the same comprehensive effects on their own.
Next Steps in Immune Rejuvenation Research
Looking ahead, the team plans to test the approach in additional animal models and to explore whether other signalling factors could further improve immune restoration. They also intend to study how this treatment influences other immune cells, including B cells, to better understand its broader impact on the immune system.