Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection.
OBJECTIVE
The mechanisms by which Foxp3+ T regulatory cells (Treg) accumulate in HCV infected livers are not known. Here, we studied the role of chemokines CCL17 and CCL22 in this process.


METHODS
Chemokine mRNA levels were determined by qPCR in liver biopsies from 26 HCV chronically infected patients (CHC), 11 patients with treatment-induced sustained virological response (SVR), 16 patients with other liver diseases unrelated to HCV, and 24 normal livers. Double-immunofluorescence Foxp3/CD3 or CD11c/CCL22 was performed in liver sections. Chemokine production by monocyte-derived dendritic cells (MDDC) co-cultured with uninfected or HCV-JFH1 infected Huh7 cells was measured by qPCR and ELISA. Chemotactic activity of culture supernatants was also tested.


RESULTS
Foxp3+ Treg were increased in CHC livers as compared to controls. Patients with CHC showed elevated intrahepatic levels of CCL17 mRNA compared to normal livers or livers from subjects with SVR or other forms of liver disease. Intrahepatic CCL22 expression was also higher in CHC than in healthy subjects or SVR patients but similar to that observed in other liver diseases. Dendritic cells producing CCL22 could be found inside the hepatic lobule in CHC patients. Contact between MDDC and HCV-JFH1-infected Huh7 cells induced the expression of CCL17 and CCL22 in a process partially dependent on ICAM-1. Transwell experiments showed that upregulation of these chemokines enhanced Treg migration.


CONCLUSIONS
Contact of HCV-infected cells with dendritic cells induces the production of Treg-attracting chemokines, an effect which may favour liver accumulation of Treg in CHC. Our findings contribute to explain the mechanism by which HCV escapes the immune response and thus reveals novel therapeutic targets.
Gene Therapy and Hepatology Area, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
José-Ignacio
JI
Riezu-Boj
Esther
E
Larrea
Rafael
R
Aldabe
Laura
L
Guembe
Noelia
N
Casares
Eva
E
Galeano
Iciar
I
Echeverria
Pablo
P
Sarobe
Ignacio
I
Herrero
Bruno
B
Sangro
Jesús
J
Prieto
Juan-José
JJ
Lasarte
D001483:Base Sequence; D016022:Case-Control Studies; D002448:Cell Adhesion / Q000276:immunology; D054414:Chemokine CCL17 / Q000096:biosynthesis* / Q000235:genetics*; D054422:Chemokine CCL22 / Q000096:biosynthesis* / Q000235:genetics*; D018920:Coculture Techniques; D015331:Cohort Studies; D017931:DNA Primers / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016174:Hepacivirus / Q000276:immunology* / Q000472:pathogenicity*; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000473:pathology / Q000821:virology; D006801:Humans; D008099:Liver / Q000276:immunology / Q000473:pathology / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation
C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D017931:DNA Primers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger