Complement Protein C1q: an Immunological Rheostat That Sculpts the Innate and Adaptive Immune Response During the Phagocytosis of Dying Cells
- Author(s): Clarke, Elizabeth Victoria
- Advisor(s): Tenner, Andrea J
- et al.
Deficiency in C1q, the recognition component of the classical complement cascade and a key opsonin involved in apoptotic cell clearance, leads to lupus-like autoimmune diseases characterized by auto-antibodies to self proteins and aberrant T and B cell activation. Studies have suggested that these pathological consequences may result from impaired clearance of apoptotic cells. To investigate how C1q may modulate inflammation resulting from diminished apoptotic cell clearance, I applied a novel system consisting entirely of primary human cells: human monocyte-derived macrophages (Mac) and dendritic cells (DC), ingesting autologous apoptotic human lymphocytes (C1q-polarized Mac; or C1q-polarized DC), and either autologous or allogeneic human T cells. This physiologically relevant experimental system enabled characterization of the C1q-polarized Mac or C1q-polarized DC functional phenotype and subsequent Mac and DC-mediated T cell activation, avoiding the caveats of other systems using either transformed cell lines or non-physiologic presentation of C1q. The results demonstrate that C1q influences intracellular signaling and gene expression of both secreted protein and cell surface receptors. That is, C1q-polarized Mac exhibited enhanced STAT1 phosphorylation that is correlated with attenuated NLRP3 inflammasome activation and sequential induction of type I IFN-s, IL-27, and IL-10 in LPS-stimulated Mac relative to Mac ingesting apoptotic lymphocytes alone. C1q-polarized DC also exhibited enhanced IL-27 expression relative to DC ingesting apoptotic lymphocytes without C1q. Under the same conditions C1q-polarized Mac showed suppressed induction of CD40 and enhanced expression of PD-L1 and PD-L2 expression while C1q-polarized DC exhibited reduced CD86 induction and elevated PD-L2 and CD39 expression relative to DC ingesting apoptotic cells alone. Finally, C1q-polarized Mac reduced allogeneic and autologous Th17 and Th1 subset proliferation, and initiated a trend towards increased regulatory T cell proliferation relative to Mac ingesting LAL alone. Moreover, relative to DC ingesting AC in the absence of C1q, C1q-polarized DC decreased autologous Th17 and Th1 proliferation. These data demonstrate that a functional consequence of C1q-polarized Mac and DC is the regulation of T effector cell activation, thereby "sculpting" the adaptive immune system to avoid autoimmunity while clearing dying cells. Importantly, these studies identify novel target pathways for therapeutic intervention in SLE and other inflammatory autoimmune diseases.