Irina Shchukina, Carlos J. Rodríguez-Hernández, Heather S. Ruiz, Maksim Kleverov, Rachel L. Mintz, Katsutaka Mineura, Subhadra C. Gunawardana, Sunnie Hsiung, Bishan Bhattarai, Veronika Vachova, Jan Kössl, Denis A. Mogilenko, Rachael L. Field, Tran Thao Thi Nguyen, Quazim A. Alayo, Christopher G. Huckstep, Barbora Vander Wielen, Jonathan R. Brestoff, Sheila A. Stewart, David W. Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J. Randolph, Maxim N. Artyomov
Aging strongly impacts CD8 + T cells, including the loss of naive cells and the emergence of age-associated GZMK + CD8 + T cells (T AA cells). Although T AA cells constitute a major population in aged mice, the pathway underlying their differentiation remains unknown. Here, we demonstrate that T AA cell development is cell extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a TNF Δ69AU/+ mouse model, we show that low-grade inflammation accelerates CD8 + T cell aging and promotes early accumulation of T AA cells. Analysis of T AA cell heterogeneity further identifies a progenitor subpopulation enriched in the aged adipose tissue. Finally, heterochronic transplantation experiments suggest that the aged adipose tissue can serve as a systemic source of T AA cells and contribute to the conversion of young CD8 + T cells into the aged phenotype. Together, these findings indicate that aged non-lymphoid tissues actively drive CD8 + T cell remodeling and identify adipose tissue as an important niche shaping immune aging.