Lymphoid tissue peripheral tissue

Hematopoietic stem cell

Monocyte/ dendritic cell precursor

Monoblast

Monocyte

Monocyte/ dendritic cell precursor

Monoblast

Monocyte

Macrophage

FIGURE 2-2 Maturation of mononuclear phagocytes and dendritic cells. Both dendritic cells and monocytes arise from a common precursor cell of the myeloid lineage in the bone marrow, and differentiation into monocytes or dendritic cells is driven by the cytokines monocyte colony-stimulating factor and Flt3 ligand, respectively (not shown). Dendritic cells further differentiate into subsets, the two major being conventional dendritic cells and plasmacytoid dendritic cells. Some dendritic cells may arise from monocytes in inflamed tissues. When blood monocytes are recruited into tissues, they become macrophages. Long-lived resident macrophages are present in all tissues of the body. At least two populations of blood monocytes exist (not shown), which are precursors, respectively, of macrophages that accumulate in response to infections and macrophages that are constitutively present in normal tissues. Macrophages in tissues become activated to perform antimicrobial and tissue repair functions in response to infections and tissue injury. Macrophages differentiate into specialized forms in particular tissues. CNS, central nervous system; DC, dendritic cell.

Activation^7

Activated macrophages

Activated macrophages

Differentiation -Microglia (CNS) I ^^N, -Kupffer cells (liver)

Macrophage

-Alveolar macrophages (lung) Osteoclasts (bone)

Common (fj[ dendritic cell precursor

Conventional DC

Plasmacytoid DC

Conventional DC

Plasmacytoid DC

FIGURE 2-2 Maturation of mononuclear phagocytes and dendritic cells. Both dendritic cells and monocytes arise from a common precursor cell of the myeloid lineage in the bone marrow, and differentiation into monocytes or dendritic cells is driven by the cytokines monocyte colony-stimulating factor and Flt3 ligand, respectively (not shown). Dendritic cells further differentiate into subsets, the two major being conventional dendritic cells and plasmacytoid dendritic cells. Some dendritic cells may arise from monocytes in inflamed tissues. When blood monocytes are recruited into tissues, they become macrophages. Long-lived resident macrophages are present in all tissues of the body. At least two populations of blood monocytes exist (not shown), which are precursors, respectively, of macrophages that accumulate in response to infections and macrophages that are constitutively present in normal tissues. Macrophages in tissues become activated to perform antimicrobial and tissue repair functions in response to infections and tissue injury. Macrophages differentiate into specialized forms in particular tissues. CNS, central nervous system; DC, dendritic cell.

FIGURE 2-3 Morphology of mononuclear phagocytes. A, Light micrograph of a monocyte in a peripheral blood smear. B, Electron micrograph of a peripheral blood monocyte. (Courtesy of Dr. Noel Weidner, Department of Pathology, University of California, San Diego.) C, Electron micrograph of an activated tissue macrophage showing numerous phagocytic vacuoles and cytoplasmic organelles. (From Fawcett DW. Bloom and Fawcett: A Textbook of Histology, 12th ed. Chapman & Hall, New York, 1994. With kind permission of Springer Science and Business Media.)

FIGURE 2-3 Morphology of mononuclear phagocytes. A, Light micrograph of a monocyte in a peripheral blood smear. B, Electron micrograph of a peripheral blood monocyte. (Courtesy of Dr. Noel Weidner, Department of Pathology, University of California, San Diego.) C, Electron micrograph of an activated tissue macrophage showing numerous phagocytic vacuoles and cytoplasmic organelles. (From Fawcett DW. Bloom and Fawcett: A Textbook of Histology, 12th ed. Chapman & Hall, New York, 1994. With kind permission of Springer Science and Business Media.)

• In addition to ingesting microbes, macrophages also ingest dead host cells as part of the cleaning up process after infection or sterile tissue injury. For example, they phagocytose dead neutrophils, which rapidly accumulate in sites of infection or tissue death caused by trauma or interrupted blood supply. Macrophages also recognize and engulf apoptotic cells before the dead cells can release their contents and induce inflammatory responses. Throughout the body and throughout the life of an individual, unwanted cells die by apoptosis, as part of many physiologic processes, such as development, growth, and renewal of healthy tissues, and the dead cells must be cleaned up by macrophages.

• Activated macrophages secrete proteins, called cytokines, that bind to signaling receptors on other cells and thereby instruct those cells to respond in ways that contribute to host defense. For example, some cytokines act on endothelial cells lining blood vessels to enhance the recruitment of more monocytes from the blood into sites of infections, thereby amplifying the protective response against the microbes. There are many different cytokines that are involved in every aspect of immune responses. The general properties and different classes of cytokines were discussed in Chapter 1.

• Macrophages serve as APCs that display antigens to and activate T lymphocytes. This function is important in the effector phase of T cell-mediated immune responses (see Chapter 10).

• Another important function of macrophages is to promote repair of damaged tissues by stimulating new blood vessel growth (angiogenesis) and synthesis of collagen-rich extracellular matrix (fibrosis). This function is mediated by certain cytokines secreted by the macrophages that act on various tissue cells.

Macrophages are activated to perform their functions by recognizing many different kinds of microbial molecules as well as host molecules produced in response to infections. These various activating molecules bind to specific signaling receptors located on the surface of or inside the macrophage. An example of these receptors is the Toll-like receptors, which are of central importance in innate immunity and will be discussed in detail in

Chapter 4. Macrophages are also activated when receptors on their plasma membrane bind opsonins on the surface of microbes. Opsonins are substances that coat particles for phagocytosis. Examples of these opsonin receptors are complement receptors and antibody Fc receptors, discussed in Chapter 12. In adaptive immunity, macrophages are activated by secreted cytokines and membrane proteins made by T lymphocytes, discussed in Chapter 10.

Macrophages can acquire distinct functional capabilities, depending on the types of activating stimuli. The clearest example of this is the response of macrophages to different cytokines made by subsets of T cells. Some of these cytokines activate macrophages to become efficient at killing microbes, called classical activation. Other cyto-kines activate macrophages to promote tissue remodeling and repair, called alternative activation. The details of these different forms of activation, and the cytokines involved, are discussed in Chapter 10. Macrophages may also assume different morphologic forms after activation by external stimuli, such as microbes. Some develop abundant cytoplasm and are called epithelioid cells because of their resemblance to epithelial cells of the skin. Activated macrophages can fuse to form multinu-cleate giant cells.

Macrophage-like cells are phylogenetically the oldest mediators of innate immunity. Drosophila responds to infection by surrounding microbes with "hemocytes," which are similar to macrophages, and these cells phagocytose the microbes and wall off the infection by inducing coagulation of the surrounding hemolymph. Similar phagocyte-like cells have been identified even in plants.

Macrophages typically respond to microbes nearly as rapidly as neutrophils do, but macrophages survive much longer at sites of inflammation. Unlike neutrophils, macrophages are not terminally differentiated and can undergo cell division at an inflammatory site. Therefore, macrophages are the dominant effector cells of the later stages of the innate immune response, several days after infection.

Mast Cells, Basophils, Eosinophils

Mast cells, basophils, and eosinophils are three additional cells that play roles in innate and adaptive immune responses. All three cell types share the common feature of having cytoplasmic granules filled with various inflammatory and antimicrobial mediators. Another common feature of these cells is their involvement in immune responses that protect against helminths and immune responses that cause allergic diseases. We will describe the major features of these cells in this section and discuss their functions in more detail in Chapter 19.

Mast Cells

Mast cells are bone marrow-derived cells that are present in the skin and mucosal epithelium and contain abundant cytoplasmic granules filled with cytokines histamine, and other mediators. Stem cell factor (also called c-Kit ligand) is a cytokine that is essential for mast cell development. Normally, mature mast cells are not found in the circulation but are constitutively present in healthy tissues, usually adjacent to small blood vessels and nerves. Human mast cells vary in shape and have round nuclei, and the cytoplasm contains membrane-bound granules (see Fig. 2-1B). The granules contain acidic proteoglycans that bind basic dyes. Mast cells express plasma membrane receptors for IgE and IgG antibodies and are usually coated with these antibodies. When these antibodies on the mast cell surface also bind antigen, signaling events are induced that lead to release of the cytoplasmic granule contents into the extracellular space. The released contents of the granules, including cytokines and histamine, promote changes in the blood vessels that cause inflammation. Mast cells also express other activating receptors that recognize complement proteins, neuropeptides, and microbial products. Mast cells provide defense against helminths but are also responsible for symptoms of allergic diseases (see Chapter 19).

Basophils

Basophils are blood granulocytes with many structural and functional similarities to mast cells. Like other gran-ulocytes, basophils are derived from bone marrow progenitors (a lineage different from that of mast cells), mature in the bone marrow, and circulate in the blood. Basophils constitute less than 1% of blood leukocytes (see Table 2-1). Although they are normally not present in tissues, basophils may be recruited to some inflammatory sites. Basophils contain granules that bind basic dyes (see Fig. 2-1C), and they are capable of synthesizing many of the same mediators as mast cells. Like mast cells, basophils express IgG and IgE receptors, bind IgE, and can be triggered by antigen binding to the IgE. Because basophil numbers are low in tissues, their importance in host defense and allergic reactions is uncertain.

Eosinophils

Eosinophils are blood granulocytes that express cytoplasmic granules containing enzymes that are harmful to the cell walls of parasites but can also damage host tissues.

The granules of eosinophils contain basic proteins that bind acidic dyes such as eosin (see Fig. 2-1D). Like neu-trophils and basophils, eosinophils are bone marrow derived. GM-CSF, IL-3, and IL-5 promote eosinophil maturation from myeloid precursors. Some eosinophils are normally present in peripheral tissues, especially in mucosal linings of the respiratory, gastrointestinal, and genitourinary tracts, and their numbers can increase by recruitment from the blood in the setting of inflammation.

Antigen-Presenting Cells

Antigen-presenting cells (APCs) are cell populations that are specialized to capture microbial and other antigens, display them to lymphocytes, and provide signals that stimulate the proliferation and differentiation of the lymphocytes. By convention, APC usually refers to a cell that displays antigens to T lymphocytes. The major type of APC that is involved in initiating T cell responses is the dendritic cell. Macrophages and B cells present antigens to T lymphocytes in different types of immune responses, and a specialized cell type called the follicular dendritic cell displays antigens to B lymphocytes during particular phases of humoral immune responses. APCs link responses of the innate immune system to responses of the adaptive immune system, and therefore they may be considered components of both systems. In addition to the introduction presented here, APC function will be described in more detail in Chapter 6.

Dendritic Cells

Dendritic cells are the most important APCs for activating naive T cells, and they play major roles in innate responses to infections and in linking innate and adaptive immune responses. They have long membranous projections and phagocytic capabilities and are widely distributed in lymphoid tissues, mucosal epithelium, and organ parenchyma (Fig. 2-4). Dendritic cells are part of the myeloid lineage of hematopoietic cells and arise from a precursor that can also differentiate into monocytes but not granulocytes (see Fig. 2-2). Maturation of dendritic cells is dependent on a cytokine called Flt3 ligand, which binds to the Flt3 tyrosine kinase receptor on the precursor cells. Similar to macrophages, dendritic cells express receptors that recognize molecules typically made by microbes and not mammalian cells, and they respond to the microbes by secreting cytokines. The majority of dendritic cells are called conventional dendritic cells. In response to activation by microbes, conventional dendritic cells in skin, mucosa, and organ parenchyma become mobile, migrate to lymph nodes, and display microbial antigens to T lymphocytes. Thus, these cells function in both innate and adaptive immune responses and are a link between these two components of host defense. One subpopulation of dendritic cells, called plas-macytoid dendritic cells, are early cellular responders to viral infection. They recognize nucleic acids of intracel-lular viruses and produce soluble proteins called type I interferons, which have potent antiviral activities. We will discuss the role of dendritic cells as mediators of innate immunity and as APCs in Chapters 4 and 6, respectively.

Antigen-Presenting Cells for Effector T Lymphocytes

In addition to dendritic cells, macrophages and B lymphocytes perform important antigen-presenting

FIGURE 2-4 A dendritic cell. The fluorescence photomicrograph shows a bone marrow-derived dendritic cell in which class II MHC molecules appear green, highlighting the fine cytoplasmic processes characteristic of dendritic cells, and the nucleus appears blue. Class II MHC molecules are highly expressed in dendritic cells and are important for their function (see Chapter 6). (Courtesy of Scott Loughhead and Uli Van Andrian, Harvard Medical School, Boston, Massachusetts.)

FIGURE 2-4 A dendritic cell. The fluorescence photomicrograph shows a bone marrow-derived dendritic cell in which class II MHC molecules appear green, highlighting the fine cytoplasmic processes characteristic of dendritic cells, and the nucleus appears blue. Class II MHC molecules are highly expressed in dendritic cells and are important for their function (see Chapter 6). (Courtesy of Scott Loughhead and Uli Van Andrian, Harvard Medical School, Boston, Massachusetts.)

functions in CD4+ helper T cell-mediated immune responses. Macrophages present antigen to helper T lymphocytes at the sites of infection, which leads to helper T cell activation and production of molecules that further activate the macrophages. This process is important for the eradication of microbes that are ingested by the phagocytes but resist killing; in these cases, helper T cells greatly enhance the microbicidal activities of the macrophages. B cells present antigens to helper T cells in lymph nodes and spleen, which is a key step in the cooperation of helper T cells with B cells in humoral immune responses to protein antigens. These functions of macrophages and B cells will be discussed in Chapters 10 and 11. Cytotoxic T lymphocytes (CTLs) are effector CD8+ T cells that can recognize antigens on any type of nucleated cell and become activated to kill the cell. Therefore, all nucleated cells are potentially APCs for CTLs.

Follicular Dendritic Cells

Follicular dendritic cells (FDCs) are cells with membranous projections that are found intermingled in specialized collections of activated B cells, called germinal centers, in the lymphoid follicles of the lymph nodes, spleen, and mucosal lymphoid tissues. FDCs are not derived from precursors in the bone marrow and are unrelated to the dendritic cells that present antigens to T lymphocytes. FDCs trap antigens complexed to antibodies or complement products and display these antigens on their surfaces for recognition by B lymphocytes. This is important for the selection of activated B lymphocytes whose antigen receptors bind the displayed antigens with high affinity (see Chapter 11).

Lymphocytes

Lymphocytes, the unique cells of adaptive immunity, are the only cells in the body that express clonally distributed antigen receptors, each with a fine specificity for a different antigenic determinant. Each clone of lymphocytes consists of the progeny of one cell and expresses antigen receptors with a single specificity. This is why the total population of antigen receptors in the adaptive immune system is said to be clonally distributed. As we shall discuss here and in later chapters, there are millions of lymphocyte clones in the body, enabling the organism to recognize and respond to millions of foreign antigens.

The role of lymphocytes as the cells that mediate adaptive immunity was established during decades of research by several lines of evidence. One of the earliest clues about the importance of lymphocytes in adaptive immunity came from the discovery that humans with congenital and acquired immune deficiency states had reduced numbers of lymphocytes in the peripheral circulation and in lymphoid tissues. Furthermore, physicians noted that depletion of lymphocytes with drugs or irradiation impaired immune protection against infection. Experiments done mainly with mice showed that protective immunity to microbes can be adoptively transferred from immunized to naive animals only by lymphocytes or their secreted products. In vitro experiments established that stimulation of lymphocytes with antigens leads to responses that show many of the characteristics of immune responses induced under more physiologic conditions in vivo. Following the identification of lymphocytes as the mediators of humoral and cellular immunity, many discoveries were made at a rapid pace about different types of lymphocytes, their origins in the bone marrow and thymus, and the consequences of the absence of each type of lymphocyte. These discoveries relied on many tools, including genetically modified mice and reagents that selectively deplete one or another type of lymphocyte. Among the most important of these discoveries was that clonally distributed, highly diverse and specific receptors for antigens are produced by lymphocytes but not by any other types of cells. During the past two decades, there has been an enormous expansion of information about lymphocyte genes, proteins, and functions. We probably now know more about lymphocytes than about any other cells in all of biology.

One of the most interesting questions about lymphocytes has been how the enormously diverse repertoire of antigen receptors, and therefore specificities, is generated from a small number of genes for these receptors in the germline. It is now known that the genes encoding the antigen receptors of lymphocytes are formed by recombination of DNA segments during the maturation of these cells. There is a random aspect to these somatic recombination events that results in the generation of millions of different receptor genes and a highly diverse repertoire of antigen specificities among different clones of lymphocytes (see Chapter 8).

TABLE 2-2 Lymphocyte Classes

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