0An MIT study reveals how to “rejuvenate” the immune system via the liver

The problem: the involution of the Thymus

The thymus, a small organ located in front of the heart, is the primary site of T lymphocyte maturation. Here immature cells are “trained” to recognize pathogens and receive essential survival signals. However, already in early adulthood, the thymus begins to shrink, a process known as thymic involution. Around the age of 75, the organ is essentially non-functional, causing a collapse in the production of new immune defenses.

“As we age, the immune system begins to decline. We wanted to think about how to maintain this type of immune protection for a longer period of time“, explains Mirco Friedrich, former MIT postdoc and lead author of the study.

The solution: the liver as a “Synthetic Factory”

Instead of attempting to regenerate thymic tissue, the team led by Feng Zhang adopted a synthetic biology approach. The idea is to temporarily program liver cells (hepatocytes) to secrete three key factors for the maturation of T lymphocytes: DLL1, FLT-3 and IL-7.

The choice fell on the liver due to its high capacity for protein synthesis and the ease with which it can be achieved via mRNA conveyed by lipid nanoparticles. Furthermore, since all circulating blood passes through the liver, T cells can come into direct contact with locally produced rejuvenation signals.

“Ours is a more synthetic approach“, says Zhang. “We are engineering the organism to mimic the secretion of thymic factors“.

Experimental results: vaccines and immunotherapy

Tests conducted on 18-month-old mouse models (equivalent to approximately 50 human years) showed significant results. After four weeks of treatment with multiple injections of mRNA, T cell populations increased both in number and function.

The study highlighted two main benefits:

Response to vaccines: in treated mice, the population of cytotoxic T lymphocytes specific for a vaccine antigen doubled compared to controls.

Fight against tumors: in combination with checkpoint inhibitor drugs (such as those that target the PD-L1 protein), mRNA treatment dramatically improved survival rates and longevity of tumor-affected animals.

“If we can restore something as essential as the immune system, we hope we can help people stay disease-free for longer in their lives“, conclude Feng Zhang. Research now aims to identify additional signaling factors and evaluate the impact of treatment on other immune cells, such as B lymphocytes.

Cover image credits: NIAID