Sustained LAIR/ITIM expression is linked to C1Q mediated dendritic cell differentiation arrest at the monocyte to DC interface (153.35)

Abstract

Abstract LAIR-1, an immune cell receptor with ITIM motifs, is highly downregulated on DCs arising from monocyte (mono) precursors. Indicative that LAIR/ITIM signaling modulates DC growth, engaging LAIR with anti-LAIR Ab inhibits DC differentiation and sustains the growth of LAIRhi mono-mΦs. Soluble C1q also disrupts DC differentiation to yield mono-mΦs over DCs. Since C1q contains the collagen motif known to be a ubiquitous ligand for LAIR, we predicted that C1q activity on DC growth is linked to LAIR. Studies were conducted during the 3 day mono/DC interface, which denotes a key transition from innate to adaptive immunity. Flow cytometry analysis of human mono/DC precursors cultured with DC growth factors (GM-CSF+IL-4) revealed reduced levels of LAIR by 24h; by 72h, ~50% of cells dimly expressed LAIR. In contrast, when C1q was combined with GM-CSF+IL-4, most cells were LAIRhi at 72h. C1q effects were dose related peaking at 20ug/ml (physiologic). Mono/DC markers studied in parallel with LAIR confirmed DC differentiation arrest with C1q. M-CSF also sustained the growth of LAIRhi mono-mΦs. Our results identify biologic factors regulating LAIR at the critical mono/DC interface and substantiate that C1q interacts with specific ligands on mono precursors to modulate DC differentiation. C1q binds to monos via its globular heads (likely via gC1qR). Thus, Gly-Pro-Hyp motifs on the C1q collagen tail could be available to engage LAIR to promote ITIM signaling and interrupt DC growth.