CCR8 orchestrates an immunosuppressive niche in the liver to promote Echinococcus multilocularis infection.

Abstract

Echinococcus multilocularis (E. m) infection causes alveolar echinococcosis (AE), a serious zoonotic disease characterized by invasive larval growth in the liver. The parasite establishes a chronic infection, suggesting effective modulation of host immunity. Here, we investigated the role of the CCR8/CCL1 chemokine axis in shaping the hepatic immune microenvironment during E.m infection. In infected wild-type (WT) mice, chronic infection specifically activated the hepatic CCR8/CCL1 axis, which was associated with a marked accumulation of FOXP3+ regulatory T cells (Tregs). Notably, although CCR8+ T cells expanded numerically, their production of effector (IFN-γ, TNF-α, and perforin) was significantly impaired. In contrast, infected CCR8-knockout (KO) mice developed smaller hepatic lesions, exhibited a reduction in liver weight, and had significantly lower serum ALT levels. Mechanistically, CCR8 deficiency enhanced the effector functions of CD4+ and CD8+ T cells, skewing the immune response towards a Th1 phenotype, and partially reversed the immunosuppressive milieu. Our findings establish that the CCR8/CCL1 axis drives the formation of an immunosuppressive niche in the liver by recruiting both Tregs and functionally suppressed CCR8+ T cells, thereby facilitating parasite immune evasion. This study not only elucidates a pivotal mechanism of immune escape in AE but also identifies CCR8 as a promising novel immunotherapeutic target for this neglected tropical disease.