title: C1q enhances IFN-gamma production by antigen-specific T cells via the CD40 costimulatory pathway on dendritic cells.
abstract: Dendritic cells (DCs) are known to produce C1q, the initiator of the classical complement pathway. We demonstrate that murine DCs deficient in C1q (C1qa(-/-)) are poorer than wild-type (WT) DCs at eliciting the proliferation and Th1 differentiation of antigen-specific T cells. These defects result from decreased production of IL-12p70 by C1qa(-/-) DCs and impaired expression of costimulatory molecules CD80 and CD86 in response to CD40 ligation. The defective production of IL-12p70 and the reduced expression of CD80 and CD86 by C1qa(-/-) DCs were specifically mediated via CD40 ligation, as normal levels of IL-12p70 and CD80/86 were observed after ligation of Toll-like receptors (TLRs) on C1qa(-/-) DCs. CD40 ligation on C1qa(-/-) DCs, but not TLR ligation, results in decreased phosphorylation of p38 and ERK1/2 kinases. A strong colocalization of CD40 and C1q was observed by confocal microscopy upon CD40 ligation (but not TLR ligation) on DCs. Furthermore, human DCs from 2 C1q-deficient patients were found to have impaired IL-12p70 production in response to CD40L stimulation. Our novel data suggest that C1q augments the production of IL-12p70 by mouse and human DCs after CD40 triggering and plays important roles in sustaining the maturation of DCs and guiding the activation of T cells.
authors.affiliation: Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Paramita
authors.initials: P
authors.lastname: Baruah
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Dumitriu
authors.forename: Talat H
authors.initials: TH
authors.lastname: Malik
authors.forename: H Terence
authors.initials: HT
authors.lastname: Cook
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Diane
authors.initials: D
authors.lastname: Scott
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Simpson
authors.forename: Marina
authors.initials: M
authors.lastname: Botto
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D019013:CD40 Antigens / Q000378:metabolism*; D037282:Calreticulin / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D015922:Complement C1q / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000378:metabolism; D017710:Lymphocyte Transfusion; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010587:Phagocytosis / Q000276:immunology; D013154:Spleen / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology* / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D019013:CD40 Antigens; D037282:Calreticulin; D051193:Toll-Like Receptors; D018664:Interleukin-12; D015922:Complement C1q; D007371:Interferon-gamma; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases