The third class of phagocytes in the immune system is the immature dendritic cells that reside in lymphoid organs and in peripheral tissues. There are two main functional types of dendritic cells: conventional (or classical) dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). Both types of cells arise from progenitors within the bone marrow that primarily branch from cells of myeloid potential, and they migrate via the blood to tissues throughout the body and to peripheral lymphoid organs. Dendritic cells ingest and break down microbes, but, unlike macrophages and neutrophils, their primary role in immune defense is not the front-line, large-scale direct killing of microbes. A major role of cDCs is to process ingested microbes in order to generate peptide antigens that can activate T cells and induce an adaptive immune response. They also produce cytokines in response to microbial recognition that activate other types of cells against infection. cDCs are thus considered to act as a bridge between innate and adaptive immune responses. pDCs are major producers of a class of cytokines known as type I interferons, or antiviral interferons, and are considered to be part of innate immunity; they are discussed in detail later in the chapter.
Because most microorganisms enter the body through the mucosa of the gut and respiratory system, skin, or urogenital tract, macrophages in the submucosal tissues are the first cells to encounter most pathogens, but they are soon reinforced by the recruitment of large numbers of neutrophils to sites of infection. Macrophages and neutrophils recognize pathogens by means of cell-surface receptors that can discriminate between the surface molecules of pathogens and those of the host. Although they are both phagocytic, macrophages and neutrophils have distinct properties and functions in innate immunity.
MOVIE 3.1
MOVIE 3.2 lipid receptor (CD36) scavenger receptors (SR-A I/II, MARCO) mannose receptor CTLD Dectin-1 Bound material is internalized in phagosomes and broken down in phagolysosomes Macrophages have phagocytic receptors that bind microbes and their components mannose receptor Dectin-1 (˜-glucan receptor) scavenger receptor complement receptor Fc receptor complement receptor lipid receptor
The process of phagocytosis is initiated when certain receptors on the surface of the cell—typically a macrophage, neutrophil, or dendritic cell—interacts with the microbial surface. The bound pathogen is first surrounded by the phagocyte plasma membrane and then internalized in a large membrane-enclosed endocytic vesicle known as a phagosome. The phagosome fuses with one or more lysosomes to generate a phagolysosome, in which the lysosomal contents are released. The phagolysosome also becomes acidified, acquires antimicrobial peptides and enzymes, and undergoes enzymatic processes that produce highly reactive superoxide and nitric oxide radicals, which together kill the microbe (Fig. 3.2). Neutrophils are highly specialized for the intracellular killing of microbes, and contain different types of cytoplasmic granules—the primary granules and secondary granules described in Section 2-4. These granules fuse with phagosomes, releasing additional enzymes and antimicrobial peptides that attack the microbe. Another pathway by which extracellular material, including microbial material, can be taken up into the endosomal compartment of cells and degraded is receptor-mediated endocytosis, which is not restricted to phagocytes. Dendritic cells and other phagocytes can also take up pathogens by a nonspecific process called macropinocytosis, in which large amounts of extracellular fluid and its contents are ingested.