As individuals advance in age, their immune systems typically lose efficiency. The numbers of T cells diminish significantly, and the surviving cells often react more sluggishly to invading pathogens. This diminished responsiveness heightens the susceptibility of elderly people to a wide array of infections.
In an effort to counteract this decline associated with aging, researchers from MIT and the Broad Institute have pioneered a technique that temporarily reprograms liver cells to enhance T cell functionality. The primary objective of this innovation is to compensate for the waning productivity of the thymus, the specialized organ responsible for the maturation of T cells.
Through their research, the scientists employed mRNA technology to introduce three crucial factors that promote T cell viability. This methodology successfully revitalized the immune systems in mice subjects. In older mice subjected to the treatment, vaccinations led to the generation of expanded and more diverse T cell populations. Furthermore, these mice exhibited superior outcomes in response to cancer immunotherapy treatments.
The research team believes that adapting this method for human application could significantly contribute to maintaining health in aging populations.
“Restoring a vital component such as the immune system could potentially enable individuals to remain disease-free for extended periods,” stated Feng Zhang, the James and Patricia Poitras Professor of Neuroscience at MIT. Zhang holds concurrent positions in the departments of Brain and Cognitive Sciences and Biological Engineering.
Zhang also serves as an investigator at MIT’s McGovern Institute for Brain Research, a core institute member at the Broad Institute of MIT and Harvard, and an investigator with the Howard Hughes Medical Institute. He led the study as the senior author. Mirco Friedrich, a former MIT postdoc, served as the lead author on the paper, which appeared in Nature.
The Role of the Thymus and T Cell Decline in Aging
The thymus, a compact organ situated just ahead of the heart, plays a pivotal role in generating a robust reservoir of T cells. Within its structure, immature T cells undergo a rigorous selection process that fosters a broad repertoire of T cell types. Additionally, the thymus secretes cytokines and growth factors essential for T cell longevity and proliferation.
However, from early adulthood onward, the thymus undergoes a progressive reduction in size, a phenomenon known as thymic involution. This shrinkage impairs the body’s capacity to generate fresh T cells. By approximately 75 years of age, the thymus has largely ceased to function effectively.
“With advancing age, our immune defenses weaken progressively,” explains Friedrich. “Our goal was to explore strategies for sustaining this critical immune safeguard over a longer timeframe, which inspired our work on enhancing immunity.”
Prior attempts to revitalize the immune system have commonly involved circulating T cell growth factors via the bloodstream. Yet, this method frequently triggers adverse side effects. Meanwhile, alternative studies have examined the potential of transplanted stem cells to regenerate viable thymic tissue.
Creating a Transient mRNA-Driven Liver Production Site
The MIT researchers opted for an innovative pathway. They investigated the possibility of inducing the body to establish a short-term “production hub” capable of emitting the T cell-boosting signals ordinarily supplied by the thymus.
“This represents a synthetic biology strategy,” notes Zhang. “We are essentially reprogramming the body to replicate the thymus’s factor secretion profile.”
The liver was chosen as the ideal site for multiple compelling reasons. Even in aged organisms, the liver retains a remarkable ability to synthesize substantial quantities of proteins. Moreover, delivering mRNA to the liver proves far simpler compared to most other organs. Crucially, since all blood circulation passes through the liver—including streams of T cells—it serves as an optimal location for dispersing immune-enhancing signals systemically.
To construct this provisional factory, the team identified three key signaling molecules integral to T cell development. These were encoded into mRNA strands and encapsulated within lipid nanoparticles. Upon intravenous administration, these nanoparticles preferentially accumulate in the liver. Local hepatocytes absorb the mRNA payload and commence translation into the specified proteins.
The trio of factors administered included DLL1, FLT-3, and IL-7. Collectively, these molecules guide progenitor T cells through their maturation into fully functional, differentiated T cells.
Enhanced Vaccine Responses and Cancer Therapy Efficacy in Aged Mice
Mouse-based experiments yielded a range of encouraging results. In one protocol, the mRNA nanoparticles were administered to 18-month-old mice, an age equivalent to humans in their mid-50s. Given the transient nature of mRNA in vivo, the researchers administered multiple doses across a four-week period to sustain consistent hepatic production of the factors.
Post-treatment analysis revealed marked expansions in both the quantity and potency of T cell populations.
To assess impacts on vaccination efficacy, the team immunized mice using ovalbumin, a well-characterized egg white protein employed in antigen-specific immune studies. Among 18-month-old mice pretreated with the mRNA therapy prior to vaccination, the count of ovalbumin-specific cytotoxic T cells doubled relative to age-matched controls lacking the treatment.
The investigation further demonstrated that this mRNA intervention augmented cancer immunotherapy performance. Researchers pretreated 18-month-old mice with mRNA, subsequently engrafted them with tumors, and administered a PD-L1-targeting checkpoint inhibitor. This pharmaceutical aims to解除 immune suppression, empowering T cells to more aggressively target malignant cells.
Notably, mice receiving the combined regimen of checkpoint inhibitor and mRNA therapy displayed substantially elevated survival probabilities and extended lifespans compared to counterparts treated solely with the inhibitor.
Ablation studies confirmed the necessity of all three factors for achieving comprehensive immune enhancement; omitting any one failed to replicate the complete benefits. Moving forward, the researchers intend to validate the protocol in diverse animal models and identify supplementary signaling molecules that could amplify immune restoration. They also aim to evaluate effects on additional immune components, such as B cells.
Additional contributors to the paper encompass Julie Pham, Jiakun Tian, Hongyu Chen, Jiahao Huang, Niklas Kehl, Sophia Liu, Blake Lash, Fei Chen, Xiao Wang, and Rhiannon Macrae.
Funding for this work was partially provided by the Howard Hughes Medical Institute, MIT’s K. Lisa Yang Brain-Body Center, contributions from Broad Institute Programmable Therapeutics Gift Donors, the Pershing Square Foundation, the Phillips family, J. and P. Poitras, as well as an EMBO Postdoctoral Fellowship.
