Dynamic structural cell responses in the thymus to acute injury, regeneration, and age

Jahn, L. L.; Kousa, A. I.; Sikkema, L.; Flores, A. E.; Argyropoulos, K. V.; Tsai, J.; Lazrak, A.; Nichols, K.; Lee, N.; Malard, F.; Andrlova, H.; Gomes, A. L.; Velardi, E.; Youssef, S.; da Silva, M. B.; Docampo, M.; Sharma, R.; Mazoutis, L.; Setty, M.; Pe'er, D.; Manley, N. R.; Dudakov, J. A.; van den Brink, M. R.

doi:10.1101/2021.12.16.472014

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bioRxiv · 10.1101/2021.12.16.472014

Dynamic structural cell responses in the thymus to acute injury, regeneration, and age

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Abstract

The thymus is essential for establishing adaptive immunity yet undergoes age-related atrophy leading to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age. Focusing on non-hematopoietic stromal cells, and using single-cell and spatial transcriptomics, lineage-tracing, and advanced imaging, we discovered two atypical thymic epithelial cell (TEC) states that emerged with age. Age-associated (aa)TECs formed atypical high-density epithelial clusters that were devoid of thymocytes, an accretion of non-functional thymic tissue that worsened with age and exhibited features of partial epithelial-to-mesenchymal transition (EMT). In silico interaction analysis revealed that aaTEC emergence drew tonic signals from other TEC populations at baseline, acting as a sink for TEC growth factors. Following damage, aaTEC expanded substantially, further perturbing trophic pathways, and correlating with defective regeneration of the involuted thymus. These findings define a unique feature of thymic involution linked to immune aging.

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Jahn, L. L., Kousa, A. I., Sikkema, L., Flores, A. E., Argyropoulos, K. V., Tsai, J., Lazrak, A., Nichols, K., Lee, N., Malard, F., Andrlova, H., Gomes, A. L., Velardi, E., Youssef, S., da Silva, M. B., Docampo, M., Sharma, R., Mazoutis, L., Setty, M., Pe'er, D., Manley, N. R., Dudakov, J. A., van den Brink, M. R.. 2021-12-17. Dynamic structural cell responses in the thymus to acute injury, regeneration, and age. https://doi.org/10.1101/2021.12.16.472014

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