A T_reg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.

Abstract

Regulatory T (T_reg) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating T_reg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver T_reg-expressed non-protein-coding RNA), which was specifically expressed in the nucleus of T_reg cells and increased with aging. T_reg-specific deletion of Altre did not affect T_reg homeostasis and function in young mice but caused T_reg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced T_reg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic T_reg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving T_reg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and T_reg fitness in the liver of aged mice. In conclusion, the T_reg-specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the T_reg-sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults.