Résumés disponibles (91) :

OUAGUIA Laurissa (UMR CNRS 8161 éq. 06 - Nadira DELHEM)
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@mail :  ouaguialaurissa@ibl.cnrs.fr      tél. :  0618433999


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Titre de la communication :
The Hepatitis C Virus Contributes to the Aggravation of the Immunosuppressive Environment by Increasing the Suppressive Activity of Natural Regulatory T cells and Inducing the Emergence of Type 1 Regulatory T Cells.
Auteurs (et leurs adresses) de la communication :
OUAGUIA Laurissa, DELHEM Nadira CNRS- UMR 8161 - Institut de Biologie de Lille 1 rue du professeur Calmette 59021 Lille Cedex
Résumé de la communication :
Background & Aims: Infection with the hepatitis C virus (HCV) is characterized by a high risk of chronicity, which may progress to cirrhosis and development of hepatocellular carcinoma (HCC). We have shown in a previous work that natural and induced human regulatory T cells (nTreg and Tr1) play an important role in the progression of hepatitis C to HCC and are associated with the severity of viral recurrence after liver graft transplantation. However, nothing is known concerning the specific impact of HCV on these two regulatory T cell sub-populations. Our hypothesis is that HCV may promote the recruitment of regulatory T cells in the infected liver, and alter their phenotype and suppressive activity for the progression of liver pathogenesis.
Methods: Treg cells were isolated from the blood of healthy donors and infected in vitro with virus particles produced in cell culture (replicon system HCVcc/JFH-1). Internalization of viral proteins was highlighted by immunofluorescence (IF) and western blot (WB). Moreover, the expression of markers associated with phenotype and suppressive function of Treg cells was analyzed by quantitative real-time PCR (Q-PCR), flow cytometry (Facs) and WB. Proliferation and suppressive activity of infected Treg cells was analyzed by Thymidine of 3H incorporation technique (MLR). Furthermore, the cytokine secretion profile of infected Treg cells was determined by ELISA. In addition, the chemokines produced by hepatic cells and known to attract Treg were analysed by RT-QPCR. Finally, the impact of HCV on Tr1 induction from conventional T cells (Tconv: CD4+CD25-) was evaluated by RT-QPCR, Facs and ELISA.
Results: We showed that Treg infection with HCV significantly increases the expression of viral receptors and that the viral proteins (NS5A, Core, E1 and E2) are internalized into Treg. Interestingly, we also showed that viral infection raises the Treg anergy and promotes the recruitment of infected Treg cells by HCV-infected hepatocytes and primary intrahepatic fibroblasts. In addition, HCV infection induced a significant increase in the expression of markers associated with Treg cells (CD4, CD25, GITR, FOXP3 ...), thus potentiating their \"suppressive phenotype.\" These results are correlated with the functional analysis of infected Treg cells, showing (i) a significant increase in the expression of markers associated with their suppressive activity (IL-10, TGF-β1, IL-35, Tbet, FAS, PD1 , Granzyme B...), (ii) a significant increase in the secretion of immunosuppressive cytokines (IL-10, TGF-β1) and (iii) an increase in immunosuppressive function (MLR). Finally, we have shown that HCV promotes conversion of conventional T lymphocytes into induced T regulatory type 1 cells.
Conclusion: This study shows for the first time that HCV can be able to be internalized into human Treg cells and could promote Treg recruitment into the infected liver. Moreover, the fact that HCV can potentiate the suppressive function of nTreg and favor the induction of Tr1 may contribute to explain the mechanisms by which HCV escapes the immune system and promotes the progression of hepatitis C to cirrhosis and HCC.

OUAGUIA Laurissa (UMR CNRS 8161 éq. 06 - Nadira DELHEM)