A Pathogenic CD8⁺ TRM–Chemokine Axis Orchestrates Liver Fibrosis and Provides Circulating Biomarkers during Chronic Clonorchis sinensis Infection

Clonorchis sinensis, a carcinogenic hepatobiliary trematode, drives severe pathological sequelae in humans. However, the immunological mechanisms underlying its chronic persistence remain incompletely elucidated. We systematically characterized the spatiotemporal dynamics of host immune responses during long-term C. sinensis infection. Systemically, immunity evolved from an early mixed Th1/Th2/Th17 response toward eventual immune resolution. In contrast, hepatic immunity shifted from an initial Th2 bias to sustained pro-inflammatory activation, paralleling progressive liver pathology. Mechanistically, this hepatic immunopathology was driven by the expansion of CD8⁺ tissue-resident memory T (TRM) cells, which secreted high levels of CCL3, CCL4, CCL5, granzyme B, and granzyme K. Functional analyses demonstrated that CD8⁺ TRM cells orchestrated immune cell recruitment and fibroblast activation, with CD8⁺ T cell depletion significantly ameliorating liver damage. Notably, CCL4 was predominantly produced by CD8⁺ TRM cells and its serum levels correlated with hepatic pathology in both murine models and human patients with clonorchiasis. Our findings identify CD8⁺ TRM cells and CCL-mediated signaling as key drivers of chronic C. sinensis-induced liver immunopathology, highlighting promising targets for therapeutic intervention.