HBV Promotes the Recruitment of Th17 Cells via the Chemokines CCL22 and CCL17

Background: The mechanisms of T helper cell 17 (Th17) accumulation in HBV-infected livers are not known. Here, we studied the role of the chemokines CCL17, CCL20, and CCL22 in this process. Methods: Peripheral blood and liver tissues were obtained simultaneously from 30 patients with chronic HBV (CHB) infection and 15 healthy volunteers (HV) and were evaluated by flow cytometric analysis and immunohistochemistry. Chemokine production by dendritic cells (DCs) cocultured with uninfected or HBV-infected Huh7 cells was measured by qPCR and ELISA. The chemotactic activity of the culture supernatants was also tested. Findings: The Th17 cell proportions were increased in the liver and PBMCs of CHB patients compared to those in controls. CHB patients showed higher intrahepatic levels of CCL17 mRNA, CCL22 mRNA, CCR6 mRNA and CCR4 mRNA than HV. The expression of CCR6 and CCR4 on the surface of CD4+/CD8+ Th17 cells in CHB patients was also significantly higher than that in healthy volunteers. Significant correlations existed between the CCR4/CCR6 levels and both the serum ALT levels and serum HBV DNA loads. Contact between DCs and pBlue-HBV-infected Huh7 cells induced the expression of CCL17 and CCL22 in a process partially dependent on the dose of HBV DNA. However, CCL20 expression was lower in patients with CHB than in healthy subjects. Transwell experiments showed that upregulation of CCL17 and CCL22 enhanced the migration of Th17 cells. Interpretation: Contact of HBV-infected cells with DCs induces CCL17 and CCL22 chemokine production, which may favor the recruitment of Th17 cells to liver tissue in CHB. Our results reveal the mechanism of Th17 recruitment to liver tissue and thus provide new immunotherapy targets for CHB patients. Funding Statement: The authors gratefully acknowledge financial support by the National Natural Science Foundation of China (81500462 and 81872584), the Natural Science Foundation of Guangdong (2016A030313357), and the Science and Technology Planning Project of Guangdong (2016A020215215). Declaration of Interests: The authors state: "There are no conflicts of interest to declare." Ethics Approval Statement: The study protocol was approved by the ethics committee of the Third Affiliated Hospital of Sun Yat-Sen University, and all patients were required to provide written informed consent.