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Open AccessArticle

Hepatitis C Virus Improves Human Tregs Suppressive Function and Promotes Their Recruitment to the Liver

1
Université Lille, UMR 8161–M3T–Mechanisms of Tumorigenesis and Targeted Therapies, F-59000 Lille, France
2
CNRS-UMR 8161, F-59000 Lille, France
3
Institut Pasteur de Lille, F-59000 Lille, France
4
Sorbonne Université, INSERM, Institute of Cardiometabolism and Nutrition (ICAN), F-75013 Paris, France
5
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), F-75012 Paris, France
6
Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Center for Infection and Immunity of Lille, F-59000 Lille, France
7
Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié–Salpêtrière Hospital, Department of Medical Liver Transplantation, F-75013 Paris, France
*
Author to whom correspondence should be addressed.
These authors have contributed equally to this work.
Cells 2019, 8(10), 1296; https://doi.org/10.3390/cells8101296
Received: 11 July 2019 / Revised: 9 October 2019 / Accepted: 10 October 2019 / Published: 22 October 2019
(This article belongs to the Special Issue Regulatory T (Treg) Cells in Health and Diseases)
Background: The role of regulatory T cells (Tregs) is now well established in the progression of hepatocellular carcinoma (HCC) linked to Hepatitis C virus (HCV) infection. However, nothing is known about the potential interplay between Tregs and HCV. In this pilot study, we have investigated the ability of Tregs to hang HCV on and the subsequent effect on their suppressive function and phenotype. Moreover, we have evaluated how HCV could promote the recruitment of Tregs by infected primary human hepatocytes. Methods: Tregs of healthy donors were incubated with JFH-1/HCVcc. Viral inoculation was assessed using adapted assays (RT-qPCR, Flow Citometry (FACS) and Western Blot (WB). Expression of Tregs phenotypic (CD4, CD25, CD127 and Foxp3) and functional (IL-10, GZMB, TGF-β1 and IL-2) markers was monitored by RT-qPCR, FACS and ELISA. Suppressive activity was validated by suppressive assays. Tregs recruitment by infected primary hepatic cells was evaluated using Boyden Chamber. Results: Tregs express the classical HCV receptors (CD81, CLDN1 and LDLR) and some co-receptors (CD5). HCV inoculation significantly increases the suppressive phenotype and activity of Tregs, and raises their anergy by inducing an unexpected IL-2 production. Moreover, HCV infection induces the expression of chemokines (CCL17, CXCL16, and CCL20) by primary hepatic human hepatocytes and chemokine receptors (CCR4, CXCR6 and CCR6) by Tregs. Finally, infected hepatocytes have a significantly higher potential to recruit Tregs in a seemingly CCL20-dependent manner. Conclusions: Direct interaction between HCV and Tregs represents a newly defined mechanism that could potentiate HCV immune evasion and favor intratumoral recruitment contributing to HCC progression. View Full-Text
Keywords: HCV; HCV/JFH-1; regulatory T cells; chemokines; immune escape HCV; HCV/JFH-1; regulatory T cells; chemokines; immune escape
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Ouaguia, L.; Moralès, O.; Aoudjehane, L.; Wychowski, C.; Kumar, A.; Dubuisson, J.; Calmus, Y.; Conti, F.; Delhem, N. Hepatitis C Virus Improves Human Tregs Suppressive Function and Promotes Their Recruitment to the Liver. Cells 2019, 8, 1296.

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