Why do our immune systems wane with age? Impaired thymus archiTECture might be one culprit.

From The Dudakov Lab, Translational Science and Therapeutics Division

Among the diverse laboratories and research groups comprising the Hutch research community, the Dudakov Lab has carved out a well-deserved niche that can best be described as ‘the thymus people.’ Not thalamus, not thyroid—the thymus, a small organ nestled between your lungs whose job it is to teach your immune cells the difference between ‘you’ and ‘not you’ (for more details, see my previous piece). What is it about this little organ that can keep an entire laboratory of dedicated researchers busy for the foreseeable future? As Dr. Jarrod Dudakov puts it, “The thymus is a really special organ. On one hand, it’s incredibly sensitive to acute insults like infection, stress, or the radiation and chemotherapies we use to treat cancer. On the other hand, it also has a remarkable ability to repair and regenerate itself following damage, in stark contrast to many of our other organs. The kicker, though, is that this amazing regenerative capacity rapidly diminishes as we age, which is thought to contribute to the general age-associated decline in immune system function. Another way to put it is that the thymus is one of the earliest organs to show signs of aging. If we can understand the mechanisms behind this process, perhaps we can keep it from happening in the first place.”

The lab’s recent work, led by bioinformatician Dr. Anastasia Kousa and published in Nature Immunology, tackles this question head-on. To gain an in-depth view of thymic cellular composition during aging, Kousa and colleagues performed single-cell RNA sequencing (scRNA-seq) on thymus isolates from young (2 month) and old (18 month) mice. While this alone was a significant undertaking, the team took it one step further by compiling their data with all 17 publicly available thymus scRNA-seq datasets, collectively representing over 300,000 cells, and created a web-based tool named Thymosight, to allow anyone with an internet connection to explore and interact with the data. After cross-referencing these datasets and others to identify different thymic cell types based on specific gene signatures, Kousa and team had rich information about a dizzying array of cell types—fibroblasts, endothelial cells, pericytes, Schwann cells, and many others—which they could compare in young and old thymic tissue.

So, what did this analysis reveal? “For a while, we had this incredibly complex dataset that showed many changes in different thymic cell populations between young and old thymi, and we really struggled to identify and prioritize specific changes which were likely to be the most relevant,” notes Kousa. Dudakov mentions that for months he and Dr. Kousa (who is based in Edinburgh) would call every week to talk about the data, throw ideas around, and “translate the dry-lab data to wet-lab hypotheses that we could test.” After a while, it seems that this strategy paid off. In addition to finding many thymic cell types that changed in abundance or state between young and old thymi, the team found two peculiar cell types that appeared only in the samples from old thymi. These cells were of a class known as thymic epithelial cells (TECs), but they were ‘atypical’, expressing some characteristic TEC genes but missing others. Absent of any other defining characteristics, Kousa and colleagues named these cells age-associated TECs, or aaTECs. “So now we had these new cell types that only appeared in old thymi, but there was a while when we weren’t quite sure what to make of them,” notes Dudakov.

But this would all change with the help of a collaborator: Dr. Daniel Gray from the University of Melbourne, Australia. Gray’s laboratory had recently created transgenic mice in which TEC nuclei were labelled with a green fluorescent protein while other cell nuclei were labelled red. This setup—combined with state-of-the-art tissue clearing and fluorescent light sheet microscopy technologies—allows researchers unprecedented access to image the cellular architecture of intact thymic tissue. When Gray and his team started imaging thymi using their method, they were surprised to find tight clusters of TECs, which they termed high density TECs (HD-TECs), that only appeared in aged or damaged thymi and expanded over time to comprise a significant proportion of overall organ cellularity. “When we posted an earlier version of this study as a preprint, Daniel’s group reached out to us and described these HD-TECs which they were seeing. We immediately wondered whether we could actually be looking at the same thing,” describes Dudakov. A little bit of spatial transcriptomics confirmed their suspicions: the aaTECs that Kousa and Dudakov noticed in their scRNA-seq datasets and the HD-TECs that Gray and colleagues were seeing in their imaging were, in fact, the same cells!

So, aged or damaged thymus tissue appears to be characterized by the appearance of dense aaTEC clusters. If aaTECs are responsible for impairing thymic repair and regeneration, how might they accomplish such a task? A battery of computational and experimental approaches led Kousa and colleagues to their current model: aaTEC clusters act like ‘scars’ that interfere with the repopulation of thymocytes—the cell type that constitutes the majority of the thymus— following injury. aaTECs do so in at least two manners: first, by physically excluding thymocytes from their vicinity as they grow to take up more and more space, and second, by acting as a sink for critical signaling molecules necessary for the growth and differentiation of new thymocytes following damage. To be sure, more work needs to be done to conclusively identify aaTECs in human thymic tissue and verify this model; it appears that the ‘thymus people’ aren’t going to be out of jobs any time soon!

an illustration of a city in the shape of a lung- a large black hole in the center is swallowing up buildings
aaTECs in the aging thymus appear to act as ‘black holes’ which engulf the space and signaling molecules necessary for proper thymic regeneration following injury or insult. Image provided by study authors.

What should we take away from this work? On this, Kousa and Dudakov agree. “Our results really show fundamental changes in the aging thymus—not merely changes in the proportions or activity of pre-existing cell types, but the appearance of entirely new cell types that impact the function of the organ as a whole. In this way, it’s a major step forward in our understanding of how the thymus degenerates as we age and how we might one day change that.”


The spotlighted work was funded by the National Institutes of Health, the Australian National Health and Medical Research Council, the Starr Cancer Consortium, the Tri Institutional Stem Cell Initiative, The Lymphoma Foundation, The Susan and Peter Solomon Divisional Genomics Program, the Cycle for Survival and the Parker Institute for Cancer Immunotherapy, the American Society of Hematology, the DKMS Foundation for Giving Life, the Cuyamaca Foundation, the Bezos Family Foundation, the European Molecular Biology Organization, and the MSK Sawiris Foundation.

Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Jarrod Dudakov and Manu Setty contributed to this study.

Kousa, A. I., Jahn, L., Zhao, K., Flores, A. E., Acenas, D., Lederer, E., Argyropoulos, K. V., Lemarquis, A. L., Granadier, D., Cooper, K., D’Andrea, M., Sheridan, J. M., Tsai, J., Sikkema, L., Lazrak, A., Nichols, K., Lee, N., Ghale, R., Malard, F., … Dudakov, J. A. (2024). Age-related epithelial defects limit thymic function and regeneration. Nature Immunology, 25(9), 1593–1606.

David Sokolov

Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.