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

BACKGROUND AIMS

Acute liver failure (ALF) is a rare but life-threatening condition, and drug-induced liver injury (DILI), particularly acetaminophen (APAP) 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 RESULTS

We analyzed liver tissue from two independent patient cohorts with ALF and identified hepatic T cell infiltration as a prominent feature in human ALF. CD8+ T cells were characterised by zonation towards necrotic regions and an activated gene expression signature. In murine APAP-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 liver as well as a broadly activated phenotype of hepatic CD8+ T cells. In two 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 via 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.

CONCLUSION

Our study demonstrates an 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.

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