Chronic stress disrupts hepatic kynurenine pathway to subvert hepatic CD8+ T cell immunity and promote liver cancer

Chronic psychological stress is associated with liver disease mortality, yet the reasons are unclear. Here we describe a stress-responsive brain-liver regulatory circuit that impairs CD8+T cell immunity and promotes the progression of liver cancer. Specifically, psychological stress-mediated dysregulation of catecholamine/ß2-adrenergic receptor (ADRB2) signaling leads to reduced number and effector functions of liver CD8+ T cells by suppressing the expression of quinolinate phosphoribosyl transferase (QPRT) in hepatocytes and shifting hepatic Kyn metabolism from de novo nicotinamide adenine dinucleotide (NAD+) synthesis to kynurenic acid (KA) production. Notably, ADRB2/QPRT expression in human hepatocytes correlates with NAD+ and KA levels, as well as CD8+T cells frequency and function in human liver tissues. Overall design: To investigate chronic stress-induced liver CD8+T cell injury, liver CD8+T cells from control and CUMS mice were purified for RNA-seq.