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

TL;DR

The study shows that the CCR8/CCL1 pathway helps the Echinococcus multilocularis parasite suppress the immune system in the liver, and blocking it could lead to better treatments.

Contribution

The study identifies CCR8 as a novel immunotherapeutic target for alveolar echinococcosis by revealing its role in creating an immunosuppressive environment.

Findings

The CCR8/CCL1 axis recruits Tregs and functionally impaired T cells to the liver during E. multilocularis infection.

CCR8 deficiency in mice reduces liver lesions and improves immune response by enhancing CD4+ and CD8+ T cell activity.

Blocking CCR8 reverses the immunosuppressive niche, promoting a Th1 immune response against the parasite.

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.

The parasite Echinococcus multilocularis causes a devastating liver disease, forming tumor-like growths that are difficult to treat. A major reason for its success is its ability to “switch off” the body’s immune defenses in the liver. We investigated a specific communication signal in cells, known as the CCR8/CCL1 pathway, to understand how the parasite achieves this. We discovered that the parasite activates this pathway, which acts like a homing beacon for the liver. This beacon attracts two types of problematic cells: powerful immune-suppressing cells (Tregs) and, surprisingly, normal immune fighter cells (T cells) that become functionally impaired. While these fighter cells are present in large numbers, they lose their ability to attack the parasite. When we genetically removed the CCR8 signal in mice, the immune system fought back effectively. These mice had much healthier livers and smaller parasite lesions because their immune cells remained active and potent. Our work shows that blocking the CCR8 pathway can reverse the parasite’s immune-suppressing tricks, revealing a promising new strategy for treating this serious disease.

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