Hepatitis C virus non-structural protein 4 suppresses Th1 responses by stimulating IL-10 production from monocytes.
The majority of hepatitis C virus (HCV) infections become chronic, despite the presence of HCV-specific cellular and humoral immune responses. We have previously suggested that IL-10-secreting antigen-specific regulatory T cells may contribute to viral persistence, and demonstrate here that peripheral blood mononuclear cells (PBMC) from chronically HCV-infected patients secrete IL-10, but not IFN-gamma, in response to HCV nonstructural protein 4 (NS4). A neutralizing anti-IL-10 antibody restored this defective antigen-specific IFN-gamma production in vitro. Furthermore, PBMC from normal individuals secreted IL-10 in response to NS4, suggesting that cells of the innate immune system, in addition to T cells, produced IL-10 in the HCV-infected patients. Cell separation experiments revealed that the innate IL-10 was produced by blood monocytes, but not dendritic cells (DC). In addition, NS4 inhibited IL-12 production by PBMC in response to LPS and IFN-gamma, and Th1 responses to recall antigens in normal individuals. Furthermore, supernatants from NS4-stimulated monocytes inhibited LPS-induced maturation of DC and suppressed their capacity to stimulate proliferation and IFN-gamma production by allospecific T cells. Our data suggest that HCV subverts cellular immunity by inducing IL-10 and inhibiting IL-12 production by monocytes, which in turn inhibits the activation of DC that drive the differentiation of Th1 cells.
Brady
Miriam T
MT
Immune Regulation Research Group, Department of Biochemistry, Trinity College, Dublin, Ireland.
MacDonald
Angus J
AJ
Rowan
Aileen G
AG
Mills
Kingston H G
KH
D015703:Antigens, CD / Q000032:analysis; D051940:B7-2 Antigen; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000032:analysis; D009000:Monocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology*; D017361:Viral Nonstructural Proteins / Q000502:physiology*; D000097802:CD83 Antigen
D015703:Antigens, CD; D051940:B7-2 Antigen; D007136:Immunoglobulins; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D008562:Membrane Glycoproteins; D017361:Viral Nonstructural Proteins; D000097802:CD83 Antigen; C497964:CD86 protein, human; C093542:NS4 protein, hepatitis C virus