A new study suggests that depleting a subset of stem cells that overproduces myeloid cells can rescue age-related immunosenescence [1].
Thrown off balance
Immunosenescence, the gradual decline in the immune system’s abilities, is one of the hallmarks of aging [2]. Moreover, many scientists view it as one of the most consequential processes of aging, as it influences many other hallmarks.
A major sign of immunosenescence is the progressive imbalance between lymphoid and myeloid cells, the two main lineages of blood cells that originate from hematopoietic stem cells (HSCs). Lymphoid cells include T cells, B cells, and natural killer cells and are primarily involved in the adaptive immune response. Myeloid cells are comprised of monocytes, macrophages, granulocytes, and dendritic cells, and they are responsible mainly for innate immunity.
A healthy immune system needs all those elements. The problem is that at least two HSC subsets exist. One is the “balanced subset”, with its progeny fairly equally divided between lymphoid and myeloid cells. The second one is biased towards producing myeloid cells. With time, this leads to an imbalance in which the organism’s ability to fight previously unknown pathogens is diminished. This imbalance also contributes to rising levels of inflammation over time (inflammaging) and myeloid-specific diseases.
Restoring immunity by depleting stem cells
In this new study published in Nature, the researchers attempted a novel approach to this problem. They asked what would happen if they were to deplete the imbalanced HSC subset that overproduces myeloid cells.
After identifying antigens specific to my-HSC (the myeloid subset), the researchers attacked those cells with antibodies in mice. This treatment significantly depleted my-HSCs relative to bal-HSCs (the balanced subset). The researchers validated this finding by transfusing immunodepleted mice with HSCs from treated mice. These cells then proliferated into a more balanced lymphoid-myeloid population.
The researchers then treated old mice with the antibodies. By the age of 18-24 months, mice demonstrated the familiar immunophenotype with a prevalence of myeloid progenitor cells, but a single treatment significantly restored the balance for at least 16 weeks.
The treatment also increased the abundance of differentiated naive T and B cells, which are capable of recognizing new antigens. The deficit of those cells is one of the most detrimental aspects of immunosenescence [3]. Treated animals also had fewer T and B cells with signs of age-associated exhaustion.
Since myeloid bias has been implicated in inflammaging, the researchers analyzed various inflammation markers. Interestingly, two pro-inflammatory factors, IL-1α and CXCL5, were the most elevated proteins in old relative to young mice. They were also the two most dramatically decreased following the treatment.
But how does this translate into actual immunity? It is known that immunosenescence significantly dampens vaccine response [4]. The researchers infected mice with a live attenuated murine retrovirus – basically, a vaccine. They used the Friend virus, which requires a complex immune response involving several cell types, each of which is essential. As expected, young mice developed a much more robust immunity than old untreated mice, but depleting my-HSC changed the picture, significantly increasing immune response in aged animals.
The evolution connection
To understand how relevant their findings were to humans, the researchers looked in human HSCs for the same genes that characterize murine my-HSCs. Several of those genes (that is, their human homologs) were indeed upregulated. Moreover, all three markers that were targeted to deplete murine my-HSCs were also found on the cell surface of a subset of human HSCs – a hint that the remarkable success the scientists had in mice can be replicated in humans.
The researchers also offer an interesting take on the possible evolutionary origins of the lymphoid-myeloid imbalance. They hypothesize that since animals usually spend their lives in a confined geographic area, they develop immunity to all local pathogens fairly early in life, after which the ability to recognize novel pathogens is no longer needed (memory T and B cells are long-lived and can survive the whole lifetime). Conversely, producing new short-lived myeloid cells for acute innate immune responses remains crucial. Modern humans, on the other hand, by traveling and interacting with people who travel, are constantly exposed to novel pathogens, which makes the lymphoid-myeloid imbalance a serious problem.
Our results indicate that my-HSC depletion in aged mice enabled bal-HSCs to rebalance the haematopoietic system and restore youthful immune features, including increased lymphocyte progenitors and naive cells, decreased markers of lymphocyte dysfunction/exhaustion and decreased inflammatory mediators. Importantly, HSC rebalancing also improved protective immunity in aged mice to live, pathogenic retroviral infection. The mouse my-HSC antigens mark subsets of human HSCs, implicating them as candidate targets for human rejuvenation. Further research will be required to optimize conditioning protocols, possibly using combinations of antibodies against my-HSC-specific markers while considering possible effects on differentiated cells such as regulatory T cells.
Literature
[1] Ross, J. B., Myers, L. M., Noh, J. J., Collins, M. M., Carmody, A. B., Messer, R. J., Dhuey, E., Hasenkrug, K. J., & Weissman, I. L. (2024). Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature, 10.1038/s41586-024-07238-x.
[2] Gruver, A. L., Hudson, L. L., & Sempowski, G. (2007). Immunosenescence of ageing. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland, 211(2), 144-156.
[3] Tu, W., & Rao, S. (2016). Mechanisms underlying T cell immunosenescence: aging and cytomegalovirus infection. Frontiers in microbiology, 7, 218871.
[4] Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., & Kennedy, R. B. (2019). Immunosenescence and human vaccine immune responses. Immunity & ageing, 16, 1-16.
