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A feed-forward loop between niche adenosine and Gzmk⁺ CD8 T cells propagates systemic inflammaging

Guo, L.; Zheng, R.; Zhan, Q.; Yu, X.; Zhang, Q.; Yao, J.; Tan, X.; Li, X.; Zhang, O.; Liu, P.; Wang, C.; Yao, Y.; Ma, R.; Wu, X.; Wang, C.; Zhou, H.; Sun, Y.; Xiong, K.; Li, L.; Xu, H.; Jin, J.; Wu, Y.; Liu, T.; Wang, Z.; Liu, Y.; Wang, Z.-y.; Cao, W.

2026-03-20 immunology
10.64898/2026.03.18.712515 bioRxiv
Show abstract

The causal link between the aging microenvironment and T cell aging remains elusive. Here, we demonstrate that adenosine within aging tissues actively reprograms CD8+ T cells into a pro-aging Granzyme K+ (Gzmk+) population. Mechanistically, senescent cells create an adenosine-rich niche via p16-dependent CD39 upregulation, triggering A2aR signaling to induce Gzmk+ T cell differentiation. Once released, Gzmk promotes systemic inflammaging through PAR1 and complement activation. Crucially, targeting this axis--either via genetic Gzmk ablation or pharmacological A2aR blockade--reverses multi-organ aging phenotypes and significantly extends healthy lifespan in mice. Human analysis reveals age-dependent Gzmk+ T cell accumulation in multi organs, while coffee intake (an A2aR antagonist) inversely correlates with plasma Gzmk levels. Our findings uncover how metabolic niche changes drive T cell aging and establish the adenosine-Gzmk axis as a pivotal therapeutic target for combating age-related diseases.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.