Th1 disabled function in response to TLR4 stimulation of monocyte-derived DC from patients chronically-infected by hepatitis C virus.
BACKGROUND
Lack of protective antibodies and inefficient cytotoxic responses are characteristics of chronic hepatitis C infection. A defect in dendritic cell (DC) function has thus been suspected, but this remains a controversial issue.


RESULTS
Here we show that monocyte-derived DC (MoDC) from chronically-infected patients can mature in response to TLR1/2, TLR2/6 or TLR3 ligands. In contrast, when stimulated with the TLR4 ligand LPS, MoDC from patients show a profound defect in inducing IFNgamma secretion by allogeneic T cells. This defect is not due to defective phenotypic maturation or to the presence of HCV-RNA in DC or monocytes but is correlated to reduced IL-12 secretion by DC. Restoration of DC ability to stimulate IFNgamma secretion can be obtained by blocking MEK activation in DC, indicating that MEK/ERK pathway is involved in the Th1 defect of MoDC. Monocytes from HCV patients present increased spontaneous secretion of cytokines and chemokines, especially MIP-1beta. Addition of MIP-1beta on healthy monocytes during differentiation results in DC that have Th1 defect characteristic of MoDC from HCV patients, suggesting that MIP-1beta secretion by HCV monocytes participates in the Th1 defect of DC.


CONCLUSIONS
Our data indicate that monocytes from HCV patients are activated in vivo. This interferes with their differentiation into DC, leading to deficient TLR4 signaling in these cells that are enable to induce a Th1 response. This specific defect is linked to the activation of the MEK/ERK pathway.
Inserm, U851, Lyon, France. laure.perrin@inserm.fr
Laure
L
Perrin-Cocon
Sophie
S
Agaugué
Olivier
O
Diaz
Béatrice
B
Vanbervliet
Sandra
S
Dollet
Aurélie
A
Guironnet-Paquet
Patrice
P
André
Vincent
V
Lotteau
D003713:Dendritic Cells / Q000276:immunology*; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D009000:Monocytes / Q000276:immunology*; D012367:RNA, Viral / Q000097:blood; D018417:Th1 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D019562:Viral Load
D012367:RNA, Viral; D051197:Toll-Like Receptor 4