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bioRxiv · 10.1101/2025.07.11.664388

Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment

Shchukina, I.·Rodriguez-Hernandez, C.·Ruiz, H. S.·Kleverov, M.·Mintz, R. L.·Mineura, K.·Gunawardana, S. C.·Hsiung, S.·Vachova, V.·Kossl, J.·Vander Wielen, B.·Mogilenko, D. A.·Huckstep, C. G.·Piston, D. W.·Egawa, T.·Kreisel, D.·Randolph, G. J.·Artyomov, M. N.
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Abstract

Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8+ T cells, including a marked decline in naive cells and the emergence of age-associated GZMK+ CD8+ T cells (TAA cells). Although TAA cells make up a significant fraction of the aged CD8+ T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that TAA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel TNF{Delta}69AU/+ mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8+ T cell aging and promotes early accumulation of TAA cells. Through detailed analysis of TAA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue. Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8+ T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8+ T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.

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Shchukina, I., Rodriguez-Hernandez, C., Ruiz, H. S., Kleverov, M., Mintz, R. L., Mineura, K., Gunawardana, S. C., Hsiung, S., Vachova, V., Kossl, J., Vander Wielen, B., Mogilenko, D. A., Huckstep, C. G., Piston, D. W., Egawa, T., Kreisel, D., Randolph, G. J., Artyomov, M. N.. 2025-07-17. Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment. https://doi.org/10.1101/2025.07.11.664388

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