2-13 Ingestion of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins.
The most important action of complement is to facilitate the uptake and destruction of pathogens by phagocytic cells. This occurs by the specific recognition of bound complement components by complement receptors (CRs) on phagocytes. These complement receptors bind pathogens opsonized with complement components: opsonization of pathogens is a major function of C3b and its proteolytic derivatives. C4b also acts as an opsonin but has a relatively minor role, largely because so much more C3b than C4b is generated.
The known receptors for bound complement components C5a and C3a are listed, with their functions and distributions, in Fig. 2.30. The C3b receptor CR1, described in Section 2-10, is a negative regulator of complement activation (see Fig. 2.27). CR1 is expressed on many types of immune cells, including macrophages and neutrophils. Binding of C3b to CR1 cannot by itself stimulate phagocytosis, but it can lead to phagocytosis in the presence of other immune mediators that activate macrophages. For example, the small complement fragment C5a can activate macrophages to ingest bacteria bound to their CR1 receptors (Fig. 2.31). C5a binds to another receptor expressed by macrophages, the C5a receptor, which has seven membrane-spanning domains. Receptors of this type transduce their signals via intracellular guanine-nucleotide-binding proteins called G proteins and are known generally as G-protein-coupled receptors (GPCRs); they are discussed in Section 3-2. C5L2 (GPR77), expressed by neutrophils and macrophages, is a
Fig. 2.30 Distribution and function of cell-surface receptors for complement proteins. A variety of complement receptors are specific for bound C3b and its cleavage products (iC3b and C3dg). CR1 and CR3 are important in inducing the phagocytosis of bacteria with complement components bound to their surface. CR2 is found mainly on B cells, where it is part of the B-cell co-receptor complex CR1 and CR2 share structural features with the complement-regulatory proteins that bind C3b and C4b. CR3 and CR4 are integrins composed of integrin β2 paired with either integrin αM (CD11b) or integrin αX (CD11c), respectively (see Appendix II); CR3, also called Mac-1, is also important for leukocyte adhesion and migration, as we shall see in Chapter 3, whereas CR4 is only known to function in phagocytosis. The receptors for C5a and C3a are seven-span G-protein-coupled receptors. FDC, follicular dendritic cells; these are not involved in innate immunity and are discussed in later chapters.
Fig. 2.31 The anaphylatoxin C5a can enhance the phagocytosis of microorganisms opsonized in an innate immune response. Activation of complement leads to the deposition of C3b on the surface of microorganisms (left panel). C3b can be bound by the complement receptor CR1 on the surface of phagocytes, but this on its own is insufficient to induce phagocytosis (center panel). Phagocytes also express receptors for the anaphylatoxin C5a, and binding of C5a will now activate the cell to phagocytose microorganisms bound through CR1 (right panel).