The α7β0 isoform of the complement regulator C4b-binding protein induces a semimature, anti-inflammatory state in dendritic cells

Rut Olivar, Ana Luque, Naranjo Gómez Mar, Josep Quer, Pablo García De Frutos, Francesc E. Borràs, Santiago Rodríguez De Córdoba, Anna M. Blom, Josep M. Aran

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23 Citations (Scopus)


The classical pathway complement regulator C4b-binding protein (C4BP) is composed of two polypeptides (α- and β-chains), which form three plasma oligomers with different subunit compositions (α7β1, α7β0, and α6β1). We show in this article that the C4BP α7β0 isoform (hereafter called C4BP[β-] [C4BP lacking the β-chain]), overexpressed under acute-phase conditions, induces a semimature, tolerogenic state on human monocyte-derived dendritic cells (DCs) activated by a proinflammatory stimulus. C4BP isoforms containing β-chain (α7β1 and α6β1; C4BP[b+]) neither interfered with the normal maturation of DCs nor competed with C4BP(β-) activity on these cells. Immature DCs (iDCs) treated with C4BP(β -) retained high endocytic activity, but, upon LPS treatment, they did not upregulate surface expression of CD83, CD80, and CD86. Transcriptional profiling of these semimature DCs revealed that treatment with C4BP(β-) prevented the induction of IDO and BIC-1, whereas TGF-β1 expression was maintained to the level of iDCs. C4BP(β -)-treated DCs were also unable to release proinflammatory Th1 cytokines (IL-12, TNF-α, IFN-γ, IL-6, IL-8) and, conversely, increased IL-10 secretion. They prevented surface CCR7 overexpression and, accordingly, displayed reduced chemotaxis, being morphologically indistinguishable from iDCs. Moreover, C4BP(β-)-treated DCs failed to enhance allogeneic T cell proliferation, impairing IFN-γ production in these cells and, conversely, promoting CD4+CD127 low/neg CD25highFoxp3+ T cells. Deletion mutant analysis revealed that the complement control protein-6 domain of the α-chain is necessary for the tolerogenic activity of C4BP(β -). Our data demonstrate a novel anti-inflammatory and immunomodulatory function of the complement regulator C4BP, suggesting a relevant role of the acute-phase C4BP(β-) isoform in a number of pathophysiological conditions and potential applications in autoimmunity and transplantation. © 2013 by The American Association of Immunologists, Inc.
Original languageEnglish
Pages (from-to)2857-2872
JournalJournal of Immunology
Issue number6
Publication statusPublished - 15 Mar 2013


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