Introduction
Aging affects all parts of our body, including our immune system. It has been known that memory T cells play a major role in immune defense by remembering previous infections and make rapid responses to new infections. Recently, researchers from St. Jude Children’s Research Hospital and the University of Minnesota have made a surprising discovery regarding how memory T cells age. Their study found out that memory T-cells have unique ability to defy aging. They have “epigenetic clocks” which can track their replication history, distinct from host age. The blog post will continue disucssing their ability based on following contents.
T-cells and epigenetic clocks
Aging often means the progression of cells’ dysfunction, with aging metrics gradually reach a limit of maximum lifespan. Markers of aging, such as changes in telomere length and mutations in somatic cells, are commonly associated with cellular aging and lifespan. However, memory T cells have a unique ability to maintain telomere length during rounds of replication. Then it comes the queston: Are memory T cells able to age independently of the lifespan of their host, or are they constrained by it?
To understand that, the research team created a model in which they transferred T cells from generation to generation, across lifetimes of mice. The key finding was that T cells do not get younger or “reset their age” upon transfer into a new host. Instead, T cells appear to have their own internal clock, which keeps track of their replication history. This clock doesn’t depend on the age of the host organism but instead reflects the T cells’ own activity.
The “clock” that the researchers observed is based on DNA methylation. It’s a type of epigenetic modification where methyl groups attach to some certain sites on DNA. Researchers observed that memory T cells accumulate these methylation marks not based on the age of the organism but rather on the cell’s own replicative history. This means that the memory T cells can have a record of their histroy of dividing due to immune challenges, independent from the host’s age. It’s “ticking” independently!
The Mouse Model Demonstrating T Cell Aging Across Multiple Lifetimes
The mouse model mentioned earlier was unique and interesting. The researchers used a model involving CD8+ cells. These cells were repeatedly exposed to various prime–boost immunizations with three different strains of vesicular stomatitis virus(VSV) (VSVnj, VVn, and VSVind), with 30 versus 60 day intervals between infections. Following this, the VSV-specific CD8+ T cells were transferred into naive (unexposed) mice. This adoptive transfer and repeated boosting cycle continued for up to 16 generations, effectively creating memory T cells that persisted over what could be considered 0.5 to 4 times the typical lifespan of a mouse (with a mouse lifespan averaging 2.5 years).
Whole-genome bisulfite sequencing showed that these “memory-loaded” (ML) T cells showed distinct DNA methylation patterns compared to young memory T cells, with some regions becoming heavily methylated in age-related patterns. These differentially methylated regions (DMRs) were enriched in cell cycle regulatory genes, including Cdkn2a and Cdkn2b that correlate to cell aging and cancer. This suggested that T cell aging is tied to their own proliferative history and these cells can keep an independent record of their “age” beyond the lifespan of their host. Despite undergoing extensive replication across multiple lifetimes in the mouse model, memory T cells did not show signs of malignant transformation. Although having approximately four organismal lifetimes, T cells didn’t show malignant outgrowth identified. By selectively excluding certain cancer-associated promoters from hypermethylation, these T cells maintain stable and controlled proliferation.
Cancerous T Cells appear hundreds of years old in young patients
Another intersting part of the study was examining T cells from pediatric patients with T cell acute lymphoblastic leukemia (T-ALL). Using DNA methylation profiles and the Horvath epigenetic clock, they assessed age estimates for cancerous T cells from T-ALL, B cell acute lymphoblastic leukemia (B-ALL), acute myeloid leukemia (AML) and melanoma. These cancerous T cells showed accelerated aging, with epigenetic markers that made them appear as though they had aged for hundreds of years. This is unusual because the patients were young, yet their T cells looked extremely “old” in terms of methylation. This again suggests that T-cells aging system is independent from host’s age.
Conclusion
To conclude, T cells have unique epigenetic clocks that track their aging independently from the host. With specific epigenetic mechanisms, T cells remain functional and cancer-resistent over time. With further understanding of this mechanism, we can have therapeutic approaches for halting or reversing age-associated impairments.
Reference
Mi, T., Soerens, A. G., Alli, S., Kang, T. G., Anoop Babu Vasandan, Wang, Z., Vaiva Vezys, Kimura, S., Iacobucci, I., Baylin, S. B., Jones, P. A., Hiner, C., Mueller, A., Goldstein, H., Mullighan, C. G., Zebley, C. C., Masopust, D., & Youngblood, B. (2024b). Conserved epigenetic hallmarks of T cell aging during immunity and malignancy. Nature Aging, 4(8), 1053–1063. https://doi.org/10.1038/s43587-024-00649-5
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