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

ABSTRACT Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8 + T cells, including a marked decline in naïve cells and the emergence of age-associated GZMK + CD8 + T cells (T AA cells). Although T AA 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 T AA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel TNF Δ69AU/+ mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8 + T cell aging and promotes early accumulation of T AA cells. Through detailed analysis of T AA 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.