Evidence that a C1q/C1qR system regulates monocyte-derived dendritic cell differentiation at the interface of innate and acquired immunity

Abstract

Growing evidence shows that C1q modulates the growth and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because C1q regulates both innate and acquired immune responses, we postulated that C1q modulates the transition from monocytes to DCs, i.e. the interface between innate and acquired immunity. Human peripheral blood monocytes cultured with soluble C1q and DC growth factors (GM-CSF + IL-4) failed to down-regulate monocyte-associated (CD14, CD16) and up-regulate DC-associated (CD83, CD86) markers. Impaired DC differentiation was not due to apoptosis; further analysis revealed the development of CD14 hi CD11c hi CD16 +/− cells that have previously been associated with both innate and acquired immunity. Monocyte-DC precursors expressed gC1qR, the receptor for globular heads of C1q, from the outset, while cC1qR, the receptor for the collagen tails of C1q, was expressed at low levels. Notably, the binding pattern of monoclonal antibodies specific to the globular heads of C1q indicated that C1q is bound to monocytes via globular heads, presumably through gC1qR. Moreover, gC1qR levels decreased, while cC1qR levels were dramatically amplified as monocytes differentiated into immature DC. Thus, specific C1q/C1q receptor (R) interactions may control the transition from the monocyte state (innate immunity) toward the professional antigen-presenting cell state (adaptive immunity).

C1q limits dendritic cell differentiation and activation by engaging LAIR-1

“…Although C1q deficiency in SLE has led to the concept that complement-independent functions of C1q include maintenance of immune tolerance, the mechanism(s) by which C1q deficiency contributes to SLE remains poorly defined, as does the means by which C1q sustains immune homeostasis in general. Because excessive immunological activation is thought to be driven by monocyte-derived DCs and pDCs in SLE, and because LAIR-1 and C1q have been independently reported to inhibit functions of both DC subtypes in a similar fashion (4,5,7,14,15), we propose that defects in C1q and LAIR-1 interactions contribute to immune pathology in this disease.…”

“…C1q not only opsonizes apoptotic debris to prevent SLE (1, 6) but suppresses IFN-α production by plasmacytoid dendritic cells (pDCs) in SLE (4,5). Reports that C1q engages cellular C1q receptors to inhibit differentiation of monocytes to DCs (7,8) provide further evidence that C1q may directly interact with immune cells to induce tolerance and inhibit autoimmunity.…”

“…LAIR-1 ligation, like C1q, inhibits molecular processes required for GM-CSF-and IL-4-driven monocyte-to-DC differentiation and Toll-like receptor (TLR)-induced IFN-α production by pDCs (7,8,14,15). Evidence that disrupted LAIR-1-mediated immune silencing leads to a loss of self-tolerance in disease settings includes deficient LAIR-1 expression on pDCs and B cells in SLE, correlating with increased IFN-α production and defective regulation of B-cell antibody secretion, respectively, and increased levels of LAIR-2 (a soluble LAIR-1 inhibitor) in rheumatoid arthritis (14,16,17).…”

Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice

“…It has also been suggested that p32 interaction with its ligands may control the differentiation of inflammatory cells, such as macrophages and dendritic cells (27). Regardless of what its pathophysiological roles might be, it is clear that cell surface p32 expression and high LyP-1 binding are potentially useful markers for a class of inflammatory cells associated with atherosclerotic plaques and tumors.…”

DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

“…15 Although both gC1qR and cC1qR lack a consensus motif for a transmembrane segment, each has been shown to recruit signaling partners with transmembrane domains. For example, some putative signaling partners for cC1qR include CD91 on monocytes, 16 8,9,24,25 However, whereas both C1q receptors are present on the surface of immature DCs (iDCs), little is known about their possible signaling partners on these cells.iDCs, but not mature DCs, are a primary source of active C1q. 1,26 Human monocyte-derived iDCs express high levels of both gC1qR and cC1qR, and their surface levels decrease in a maturation-dependent manner.…”