C1q enhances IFN-gamma production by antigen-specific T cells via the CD40 costimulatory pathway on dendritic cells.
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.
Baruah
Paramita
P
Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College London, London, United Kingdom.
Dumitriu
Ingrid E
IE
Malik
Talat H
TH
Cook
H Terence
HT
Dyson
Julian
J
Scott
Diane
D
Simpson
Elizabeth
E
Botto
Marina
M
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
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