Complement protein C1q bound to apoptotic cells suppresses human macrophage and dendritic cell-mediated Th17 and Th1 T cell subset proliferation.

A complete genetic deficiency of the complement protein C1q results in SLE with nearly 100% penetrance in humans, but the molecular mechanisms responsible for this association have not yet been fully determined. C1q opsonizes ACs for enhanced ingestion by phagocytes, such as M phi and iDCs, avoiding the extracellular release of inflammatory DAMPs upon loss of the membrane integrity of the dying cell. We previously showed that human monocyte-derived M phi and DCs ingesting autologous, C1q-bound LALs (C1q-polarized M phi and C1q-polarized DCs), enhance the production of anti-inflammatory cytokines, and reduce proinflammatory cytokines relative toM phi or DC ingesting LAL alone. Here, we show that C1q-polarizedM phi have elevated PD-L1 and PD-L2 and suppressed surface CD40, and C1q-polarized DCs have higher surface PD-L2 and less CD86 relative to M phi or DC ingesting LAL alone, respectively. In an MLR, C1q-polarized M phi reduced allogeneic and autologous Th17 and Th1 subset proliferation and demonstrated a trend toward increased Treg proliferation relative to M phi ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DCs decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized M phi and DC is the regulation of Teff activation, thereby "sculpting" the adaptive immune system to avoid autoimmunity, while clearing dying cells. It is noteworthy that these studies identify novel target pathways for therapeutic intervention in SLE and other autoimmune diseases.