debtEvery species has a set lifespan, from fruit flies that live for just two weeks to tropical giant tortoises that live for almost 200 years. But while an organism’s lifespan may be limited by its biology, not all of its cells seem to follow the same rules.
2023, Immunologist at the University of Minnesota David Masops His team found that when they transferred the same population of T cells from mouse to mouse and back again, they found that up to 10 yearsThat’s about four times the lifespan of a mouse.1 These older immune cells not only survived, but remained functional: they proliferated in response to appropriate antigens and did not senesce or grow uncontrollably.
In a recently published paper, Natural agingMassops worked with immunologists Benjamin Youngblood and Caitlin Zebley To conduct research at St. Jude Children’s Research Hospital The epigenetic clock These mouse cells appeared to resist aging.2 Unlike most cells, whose clocks run in time, the T cell clock appears to keep track of proliferation events and continued to run well beyond the organism’s natural lifespan. This work raises important questions about age-related immunosenescence and T cell depletionIt may occur in association with cancer or chronic infections.3
“This is a truly fascinating mouse model and a fantastic tool to investigate the relationships between replicative history, epigenetic age, and chronological age,” they write. Andrew Yates“The study is a very interesting one,” said Robert G. Schneider, a quantitative immunologist at Columbia University who was not involved in the study. scientist.
Compared to other cells in the human (and mouse) body, T cells have a very different pattern of proliferation and proliferation. They respond to specific antigens (proteins from a particular strain of influenza virus, Streptococcus Bacteria have only a few T cells with the cellular machinery necessary to respond to this threat.”[Initially]”These cells are very rare and not abundant enough to be functionally important,” Massops says, “but when you have an infection, these cells become the fastest dividing cells in the body, dividing every six hours… [so they] Before dying, this T-cell population shrinks but remains at a much larger number than before infection, and the cells are ready to start proliferating again and become active if they encounter the same antigen again.
Massops wanted to test the limits of this proliferation capacity: “It is thought that every cell in the body can only double a certain number of times before it can essentially never divide again, a state that many people refer to as senescence.”
T cells Aging during aging, chronic infections, and cancer.4 But the mechanisms that drive senescence in these cells remain conclusively unknown. “We felt that this was something that was contextual, not just proliferation or stimulation history,” Massops says. “And we were willing to take a chance on that.”
To test this hypothesis, Massops and his team needed a system in which they could separate cell-intrinsic and cell-extrinsic factors. In a first group of mice, the researchers used a carefully timed vaccination-and-boost protocol to generate an army of memory T cells specific for a particular antigen. They then transferred some of these memory T cells into new mice, gave them a vaccine that triggered their proliferation, and started the process all over again.
“We just kept experimenting until it got ridiculous,” Masopust recalls. Ultimately, they transplanted the T cells into new mice up to 17 times over the next decade. As Masopust’s team demonstrated in a 2023 paper, these ancient cells continued to function, fulfilling their roles as needed, without succumbing to senescence or uncontrollable growth.
In this study, the researchers probed the inner workings of these cells. They found that the cells’ epigenetic clock continues to tick well beyond the lifespan of a normal mouse. As the T cells aged through multiple passages, genome-wide methylation gradually decreased, and the researchers observed changes in the epigenetic profile of several loci, including genes that control tumor suppression and tumorigenesis. These findings suggest a potential link between the clock and mechanisms that help aging T cells avoid replicative senescence, but it remains unclear whether these epigenetic changes simply record the cell’s history or actively promote longevity by altering gene expression.
The researchers were also curious about what the T cell clock records: While traditional epigenetic clocks record chronological time, the T cell clock appears to function differently, suggesting that the clock records the proliferation history of the cells rather than their age.
But does this clock run by similar rules in human T cells? In healthy people, naive T cells, which have not undergone antigen-induced proliferation events, appear young regardless of the actual age of the donor. However, in children with T-cell acute lymphoblastic leukaemia, whose cells proliferate rapidly and uncontrollably, their T cells were 100–200 years old according to the epigenetic clock, even though some of them were no older than 15 years old.
But Yates raises an important caveat, one that the researchers acknowledge in their paper: “The repetitive transplantation process may, at least in part, be selecting for established epigenetic states that confer fitness, rather than methylation changes gradually acquired over time within cell lineages. Disentangling these alternatives will be difficult,” Yates writes. In other words, it may be hard to determine the extent to which these epigenetic changes are markers of cell history, or whether cells that have acquired certain epigenetic changes are the only cells that can survive and proliferate.
Either way, Massops believes this research has a lot of potential for the future: Understanding the T cell aging process and the “rules” that govern whether aged T cells remain functional or become senescent may lead to new strategies to combat the age-related decline in immune function.
Similarly, Masopust said, “We [T cell] “We deplete T cells in a different way, and perhaps we could apply this to adoptive cell therapy, which is a newer, somewhat boutique way to cure cancer. We’ve seen some very impressive clinical results,” he added. “But one of the problems with these cells is that they need to be durable to generate enough of them, so they don’t get depleted.” By studying multi-lived T cells, which can be easily expanded and are likely to be less prone to depletion, Masopust hopes to identify strategies to evoke the same properties in cancer-fighting chimeric antigen receptor (CAR) T cells for patients.
