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

Area of Science:

• Immunology
• Molecular Biology

Background:

• C1q and LAIR-1 (leukocyte-associated Ig-like receptor 1) are implicated in inhibiting dendritic cell differentiation and Toll-like receptor activity.
• Defects in C1q and LAIR-1 are linked to systemic lupus erythematosus (SLE) susceptibility and progression.
• The inhibitory signaling partners for C1q on monocytes and DCs are not well-defined.

Purpose of the Study:

• To investigate if C1q acts as a functional ligand for LAIR-1, given C1q's collagen-like motifs and LAIR-1's role as a collagen receptor.
• To elucidate the molecular mechanisms underlying C1q's inhibitory functions on immune cells.

Main Methods:

• Binding assays were performed in cell-free systems and on cell membranes to assess C1q-LAIR-1 interactions.
• Monocytes were used to analyze the phosphorylation of LAIR-1 immunoreceptor tyrosine-based inhibitory motifs (ITIMs) upon C1q stimulation.
• Functional assays involved assessing the effects of C1q, LAIR-2, and LAIR-1 siRNA on monocyte-derived dendritic cell differentiation and plasmacytoid DC IFN-α production.

Main Results:

• C1q and its collagen tail directly associate with LAIR-1 and the soluble inhibitor LAIR-2 (CD306).
• Both C1q and its collagen tail induce phosphorylation of LAIR-1 ITIMs in monocytes.
• LAIR-2 reversed C1q-mediated inhibition of monocyte-DC differentiation and plasmacytoid DC IFN-α production.
• LAIR-1 siRNA reversed C1q-mediated inhibition of DC differentiation.

Conclusions:

• C1q is a functional ligand for LAIR-1, playing a key role in restricting immune cell differentiation and activation.
• The interaction between C1q, LAIR-1, and LAIR-2 provides novel insights into immune tolerance mechanisms.
• This discovery offers a molecular basis for understanding the role of these molecules in systemic lupus erythematosus pathogenesis.