Scientists have discovered that a cytotoxic subtype of CD4 T cells, which is enriched in old people, helps control cellular senescence. This hints at a new type of anti-senescence strategy but also suggests that an immune system can be “overly youthful.”
When generals become fighters
CD4 T cells usually behave as “generals”, directing immune attacks from behind the front lines. However, previous research suggests that some of these cells can themselves become killers under certain conditions; for instance, cytotoxic CD4 T cells are enriched in very old people, according to a study of Japanese centenarians [1].
Since aging is also associated with an increasing burden of senescent cells, scientists from the Ben-Gurion University of the Negev, in a new study published in Nature Aging, asked whether these “killer” CD4 T cells are induced by senescent cells and if they help to control senescent cells and the damage they cause.
The senescence connection
First, the researchers transferred a mixture of splenic immune cells from young mice to either young or old recipient mice and tracked what happened to the CD4 T cells. The donors and the recipients were slightly different genetically so that the researchers could follow the donor-originated cells.
After a month, the researchers analyzed the fraction of T cells expressing the “killer” phenotype, which is characterized in particular by the expression of Eomesodermin (Eomes), a transcription factor that, in T cells, helps drive a cytotoxic program. In old recipients, the transferred young CD4 T cells acquired a much higher fraction of Eomes-positive cells while other subtypes (naïve, effector, and Treg) were unchanged or reduced. T cells transplanted into old hosts also showed increased markers of exhaustion.
Interestingly, the proportion of CD4-Eomes among transferred young cells in old mice matched that of the endogenous old CD4 pool, implying that this differentiation is dictated by the environment.
Using a dye that gets diluted every time a cell divides, the team found that donor-derived CD4-Eomes were created by extensive cell division. That shows that the old, senescent environment actively drives young CD4 T cells to proliferate and then differentiate into this cytotoxic state.
Treating old recipients with the senolytic drug navitoclax before transfer reduced liver senescence markers and lowered the ratio of transferred/host CD4-Eomes cells without altering other CD4 subsets. This suggests that the senescent cell burden specifically drives the expansion and differentiation of CD4-Eomes cells.
The researchers then created genetically modified mice with tamoxifen-inducible CD4 T cell-specific Eomes deficiency. When Eomes knockout was triggered in 20-month-old mice, CD4-Eomes frequencies dropped, and the animals developed worse grip strength and reduced spontaneous activity. The livers of Eomes-KO mice showed increased accumulation of senescent cells, both immune and non-immune.
Next, the team placed 15-month-old mice on a long-term tamoxifen treatment (40 weeks). As a result, in the Eomes-KO cohort, survival dropped precipitously compared to Eomes-normal animals. However, in Eomes-KO mice treated with navitoclax, survival rates were closer to controls. These results suggest that CD4-Eomes cells in old mice restrain senescent cell accumulation and help preserve function and lifespan.
Is appropriate better than young?
In addition to aging, increased senescent cell accumulation also occurs in various diseases. To investigate the role of CD4 Eomes cells in a disease setting, the researchers used a mouse model of liver cirrhosis.
Eomes-KO livers had more extensive scarring and more severe fibrosis than controls as well as an increased senescent cell burden. Adding navitoclax reduced both fibrosis and senescence markers. It also reduced the frequency of CD4-Eomes in wild type mice, consistent with the idea that less senescence leads to fewer cytotoxic Eomes-positive T cells.
This is not the first recent study suggesting that simply keeping the immune system young and strong might not be an ideal anti-aging strategy. Another one recently uncovered a connection between “overly youthful” immune systems and autoimmune disease, which become more prevalent as we age [2]. In the context of this study, according to its authors, it means that a more “aged” phenotype of increased CD4-Eomes T cells may be important for countering age-related senescence.
“People say that to reverse aging and ‘rejuvenate’, we need to reset their immune system like the immune systems of people in their 20s,” said Prof. Alon Monsonego, a senior author. “However, our research shows that this might not be the case. People don’t need a super-charged immune system; they need one that is working properly and appropriate for their stage in life. So, one of the ‘axioms’ of how to reduce aging may be incorrect.”
“The authors integrate rigorous in vivo and ex vivo approaches to make a compelling case that immune-mediated senescence surveillance is not a peripheral feature of aging biology, but a central regulatory axis,” said Dr. Amit Sharma, a senior researcher from Lifespan Research Institute, who was not involved in this study. “For years, I’ve believed that unraveling this immune–senescence interface is key not only to understanding the biology of aging but also to developing effective therapeutics for age-related diseases. This paper strongly reinforces that view.”
Literature
[1] Hashimoto, K., Kouno, T., Ikawa, T., Hayatsu, N., Miyajima, Y., Yabukami, H., … & Carninci, P. (2019). Single-cell transcriptomics reveals expansion of cytotoxic CD4 T cells in supercentenarians. Proceedings of the National Academy of Sciences, 116(48), 24242-24251.
[2] Weyand, C. M., & Goronzy, J. J. (2025). Sustained immune youth risks autoimmune disease in the aging host. Nature Aging, 5(8), 1404-1414.
View the article at lifespan.io
