HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production.
Dendritic cells (DCs) isolated from patients with chronic hepatitis C virus (HCV) infection display an impaired capacity to generate type 1 CD4(+) T cell immunity. Several reports have described an immunomodulatory function for the HCV core protein, and circulating core has been shown to associate with the putative gC1q receptor, gC1qR, expressed on host immune cells. However, the molecular mechanism(s) of HCV core-mediated DC dysfunction has not been defined. Herein, ligation of gC1qR on human monocyte-derived DCs (MDDCs) with HCV core or anti-gC1qR agonist antibody was shown to inhibit TLR-induced IL-12 production but not the production of other TLR-stimulated cytokines. Furthermore, engagement of gC1qR on MDDCs resulted in reduced IFN-gamma secretion by allogeneic CD4(+) T lymphocytes during mixed lymphocyte culture. Differentiation of CD4(+) T cells cocultured with HCV core- or anti-gC1qR antibody-treated MDDCs was also skewed toward production of Th2 cytokines, including IL-4. Importantly, that addition of IL-12 rescued IFN-gamma production and Th1 differentiation by CD4(+) T cells. Therefore, engagement of gC1qR on DCs by HCV core limits the induction of Th1 responses and may contribute to viral persistence.
Waggoner
Stephen N
SN
Department of Microbiology, Beirne Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22903, USA
Hall
Caroline H T
CH
Hahn
Young S
YS
D000911:Antibodies, Monoclonal / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis*; D007959:Lymphocyte Culture Test, Mixed; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D010641:Phenotype; D011485:Protein Binding; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology; D014758:Viral Core Proteins / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C087299:C1QBP protein, human; D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D018664:Interleukin-12