Systematic understanding of immune aging on a whole-body scale is currently lacking. We characterized age-associated alterations in immune cells across multiple mouse organs using single-cell RNA and antigen receptor sequencing and flow cytometry-based validation. We defined organ-specific and common immune alterations and identified a subpopulation of age-associated granzyme K (GZMK)-expressing CD8⁺ T (Taa) cells that are distinct from T effector memory (Tem) cells. Taa cells were highly clonal, had specific epigenetic and transcriptional signatures, developed in response to an aged host environment, and expressed markers of exhaustion and tissue homing. Activated Taa cells were the primary source of GZMK, which enhanced inflammatory functions of non-immune cells. In humans, proportions of the circulating GZMK⁺CD8⁺ T cell population that shares transcriptional and epigenetic signatures with mouse Taa cells increased during healthy aging. These results identify GZMK⁺ Taa cells as a potential target to address age-associated dysfunctions of the immune system.

目前缺乏对全身免疫衰老的系统理解。我们使用单细胞 RNA 和抗原受体测序以及基于流式细胞术的验证来表征多个小鼠器官中与年龄相关的免疫细胞变化。我们定义了器官特异性和常见的免疫改变，并确定了表达年龄相关颗粒酶 K (GZMK) 的 CD8 ⁺不同于 T 效应记忆 (Tem) 细胞的 T (Taa) 细胞。Taa 细胞是高度克隆的，具有特定的表观遗传和转录特征，响应老化的宿主环境而发育，并表达衰竭和组织归巢的标志物。活化的 Taa 细胞是 GZMK 的主要来源，可增强非免疫细胞的炎症功能。在人类中，与小鼠 Taa 细胞共享转录和表观遗传特征的循环 GZMK ⁺ CD8 ⁺ T 细胞群的比例在健康衰老期间增加。这些结果表明 GZMK ⁺ Taa 细胞是解决与年龄相关的免疫系统功能障碍的潜在目标。