Impaired TRAIL-dependent cytotoxicity of CD1c-positive dendritic cells in chronic hepatitis C virus infection.
Dendritic cells (DCs) play a central role in antiviral immunity. Conflicting data on DC function have been reported for hepatitis C virus (HCV) infection. In addition to antigen presentation and cytokine secretion, a subset of human DCs displays direct cytotoxic activity. It has been suggested that measles virus and human immunodeficiency virus (HIV) may enhance cytotoxicity of DCs potentially leading to apoptosis of activated T cells and subsequent down-regulation of antiviral immune responses. We demonstrate that CD1c-positive myeloid DCs, but not BDCA-4-positive plasmacytoid DCs, are able to kill different target cells mainly via tumour necrosis factor-related apoptosis-inducing ligand. The ability of CD1c+ DCs to lyze target cells was found to be completely impaired in patients with chronic hepatitis C (10 chronic HCV patients vs 10 healthy controls; P < 0.001) but not in patients with primary biliary cirrhosis. Successful antiviral therapy of chronic hepatitis C rescued the cytotoxicity of DCs. Myeloid DCs of HCV patients and healthy controls had a similar phenotype and endocytotic activity, however, the frequency of mDCs in the peripheral blood was lower (P = 0.004) and the allostimulatory function was weaker (P < 0.001) in chronic hepatitis C. Thus, in contrast to HIV and measles virus studies on monocyte-derived DCs, freshly isolated myeloid DCs of patients with hepatitis C do not show an increased but a completely abolished cytotoxic activity. The impaired DC cytotoxicity could represent a novel mechanism for the increased prevalence of autoimmunity in HCV infection.
Ciesek
S
S
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Liermann
H
H
Hadem
J
J
Greten
T
T
Tillmann
H L
HL
Cornberg
M
M
Aslan
N
N
Manns
M P
MP
Wedemeyer
H
H
D000328:Adult; D018949:Antigens, CD1 / Q000032:analysis; D000954:Antigens, Surface / Q000032:analysis; D017209:Apoptosis; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000737:chemistry / Q000276:immunology*; D005260:Female; D006023:Glycoproteins / Q000032:analysis; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008105:Liver Cirrhosis, Biliary / Q000276:immunology; D008297:Male; D008875:Middle Aged; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology*
D018949:Antigens, CD1; D000954:Antigens, Surface; C437944:CD1C protein, human; D006023:Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C478196:blood dendritic cell antigen 4, human