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Blood, 9 April 2009, Vol. 113, No. 15, pp. 3485-3493.
Prepublished online as a Blood First Edition Paper on January 26, 2009; DOI 10.1182/blood-2008-06-164392.
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IMMUNOBIOLOGY
C1q enhances IFN- production by antigen-specific T cells via the CD40 costimulatory pathway on dendritic cells
Paramita Baruah1,
Ingrid E. Dumitriu1,
Talat H. Malik1,
H. Terence Cook2,
Julian Dyson3,
Diane Scott3,
Elizabeth Simpson3, and
Marina Botto1
1 Molecular Genetics and Rheumatology Section,
2 Department of Histopathology, and
3 Department of Immunology, Faculty of Medicine, Imperial College London, London, United Kingdom
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.
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