The immune system ages in complex ways, but the result of all of this complexity is chronic inflammation and incapacity, the states of inflammaging and immunosenescence. An aged immune system causes tissue dysfunction on the one hand, while failing to protect against infectious pathogens and malfunctioning cells on the other hand. Focused on one specific part of this big picture, researchers here explore the origins of a dysfunctional population of T cells that emerges in later life to contribute to overall immune dysfunction. They find that fat tissue appears important in encouraging this population to expand from its progenitor cell of origin.
In our previous work using aged mice, we identified a novel population of CD8+ T cells that accumulates across multiple tissues with age. These age-associated CD8+ T cells (TAA cells) are distinct from conventional effector and memory subsets and are also increased in the peripheral blood of older humans. At the transcriptional level, TAA cells are marked by high expression of Gzmk, a granzyme implicated in both cytolytic and non-cytolytic functions, including promotion of pro-inflammatory responses. TAA cells also exhibit co-expression of activation and exhaustion signature.
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 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.
Link: https://doi.org/10.1101/2025.07.11.664388
View the full article at FightAging
