C-C chemokine receptor type 7 (CCR7) regulates hepatic CD8⁺ T cell homeostasis and response to acute liver injury

Background and Aims: Acute liver failure (ALF) is a rare but life-threatening condition, and DILI, particularly acetaminophen toxicity, is the leading cause of ALF. Innate immune mechanisms further perpetuate liver injury, while the role of the adaptive immune system in DILI-related ALF is unclear. Approach and Results: We analyzed liver tissue from 2 independent patient cohorts with ALF and identified hepatic T cell infiltration as a prominent feature in human ALF. CD8(+) T cells were characterized by zonation toward necrotic regions and an activated gene expression signature. In murine acetaminophen-induced liver injury, intravital microscopy revealed zonation of CD8(+) but not CD4(+) T cells at necrotic areas. Gene expression analysis exposed upregulated C-C chemokine receptor 7 (CCR7) and its ligand CCL21 in the liver as well as a broadly activated phenotype of hepatic CD8(+) T cells. In 2 mouse models of ALF, Ccr7(-/-) mice had significantly aggravated early-phase liver damage. Functionally, CCR7 was not involved in the recruitment of CD8(+) T cells, but regulated their activation profile potentially through egress to lymphatics. Ccr7(-/-) CD8(+) T cells were characterized by elevated expression of activation, effector, and exhaustion profiles. Adoptive transfer revealed preferential homing of CCR7-deficient CD8(+) T cells to the liver, and depletion of CD8(+) T cells attenuated liver damage in mice. Conclusions: Our study demonstrates the involvement of the adaptive immune system in ALF in humans and mice. We identify the CCR7-CCL21 axis as an important regulatory pathway, providing downstream protection against T cell-mediated liver injury.