CD46 Plays a Key Role in Tailoring Innate Immune Recognition of Apoptotic and Necrotic Cells

Abstract

Complement is the canonical innate immune system involved in host defense and tissue repair with the clearance of cell debris. In contrast to the robust armory mounted against microbial nonselfpathogens, complement is selectively activated on altered self (i.e. apoptotic and necrotic cells) to instruct the safe demise by poorly characterized mechanisms. Our data shed new light on the role of complement C1q in sensing nucleic acids (NA) rapidly exposed on apoptotic Jurkat T cell membranes and in driving C3 opsonization but without the lytic membrane attack complex. DNA/RNasetreated apoptotic cells failed to activate complement. We found that several other apoptotic cell models, including senescent keratinocytes, ionophore-treated sperm cells, and CMK-derived platelets, stained for cleaved caspase 3 were rapidly losing the key complement regulator CD46. CD46 from nuclear and membrane stores was found to cluster into blebs and shed into microparticles together with NA, phosphatidylserine, C1q, and factor H. Classical and alternative pathways of complement were involved in the recognition of H 2 O 2 -treated necrotic cells. Membrane attack complex was detected on necrotic cells possibly as a result of CD46 and CD59 shedding into soluble forms. Our data highlight a novel and universal paradigm whereby the complement innate immune system is using two synergistic strategies with the recognition of altered self-NA and missing self-CD46 signals to instruct and tailor the efficient removal of apoptotic and necrotic cells in immunoprivileged sites.

IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells

“…2C), skews nTregs and Tconv to Tr1 secreting IL-10, which prematurely imbalances the adaptive immunity toward immune suppression. The role of C3b protein, the CD46 agonist resulting from C′ activation, in the pathogenesis of active lupus patients is also suggested by the presence in the serum of these patients of soluble CD46 (30), product of proteolytic cleavage of apoptotic cell membranes (31). As for IFN-α, by reducing nTreg and Tconv number and function, this cytokine may further enhance the risk of autoimmunity and infection.…”

Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

“…and Histones-DNA has been previously suggested to act as a C1q ligand on apoptotic cells (8). To further investigate the relevance of this interaction, surface plasmon resonance was used to analyze the binding affinity between C1q and DNA (Fig.…”

“…The aim of the current study was to investigate new ligands for C1q on the surface of apoptotic cells. So far the only widely accepted C1q ligand on dying cells is DNA, which becomes accessible already very early on apoptotic cells, even before phosphatidylserine (PS) 3 (8). However, the precise region of C1q involved in DNA binding is a matter of controversy, because both the collagen-like stalk region and the globular head region have been implicated (7, 9 -12).…”

“…These two complement inhibitors interfere with the cascade at the C3 level to minimize proinflammatory and lytic effects of full-blown complement activation. They also compensate for the loss of membrane-bound complement inhibitors such as membrane cofactor protein (MCP, CD46), which in turn, when down-regulated during apoptosis, act as an "eatme" signal for effective clearance (8). Efficient and noninflammatory clearance of dying cells is crucial to avoid autoimmune reactions.…”

Complement Receptors in Inflammation

“…Second, the alternative pathway can be initiated by nucleophilic attack of C3 directly on the surface of allergen or by Factor B (Taube et al, 2006). Third, the recognition of PAMPs and danger-associated molecular patterns (DAMPs), such as nucleic acids on apoptotic cells (Elward et al, 2005) or allergen polysaccharide, (Bito, 1977, Zimmermann et al, 1989 can activate the lectin pathway. Fourth, proteases released from inflammatory cells or direct protease activity of allergens (Maruo et al, 1997) can drive the generation of C3a and C5a.…”