Cells Of The Immune System
The cells of the immune system can be divided broadly into two main classes – myeloid and lymphoid cells
Immune cells, which are collectively called leukocytes (white blood cells), can be divided broadly into myeloid and lymphoid subsets (Figure 1.7).
Myeloid cells, which comprise the majority of the cells of the innate immune system, include macrophages (and their monocyte precursors), mast cells, dendritic cells, neutrophils, basophils, and eosinophils. All myeloid cells have some degree of phagocytic capacity (although basophils are very poorly phagocytic compared to other myeloid cell types) and specialize in the detection of pathogens via membrane or endosomal PRRs, followed by engulfment and killing of infectious agents by means of a battery of destructive enzymes contained within their intracellular granules.
Neutrophils are by far the most abundant leukocyte circulating in the bloodstream, comprising well over 50% of leukocytes, and these cells are particularly adept at phagocytosing and killing microbes. However, because of their destructive potential, neutrophils are not permitted to exit the blood and enter tissues until the necessity of their presence has been confirmed through the actions of other cells of the innate immune system (especially macrophages and mast cells), as well as soluble PRRs such as complement. As we shall see, certain myeloid cells, such as macrophages and dendritic cells, have particularly important roles in detecting and instigating immune responses, as well as presenting the components of phagocytosed microbes to cells of the lymphoid system. Broadly speaking, activated myeloid cells also have an important function in escalating immune responses through the secretion of multiple cytokines and chemokines as well as additional factors that have powerful effects on local blood vessels.
The other major class of immune cells, the lymphoid cells, comprise three main cell types, T‐lymphocytes, B‐lymphocytes, and natural killer (NK) cells. T‐ and B‐lymphocytes are the central players in the adaptive immune system and have the ability to generate highly specific cell surface receptors (T‐ and B‐cell receptors), through genetic recombination of a relatively limited number of precursors for these receptors (discussed in detail in Chapters 4 and 5). T‐cell receptors (TCRs) and B‐cell receptors (also called antibodies) can be generated that are exquisitely specific for particular molecular structures, called antigens, and can fail to recognize related antigens that differ by only a single amino acid. NK cells, although lymphocytes, play a major role within the innate immune system, but these cells also police the presence of special antigen‐presenting molecules (the aforementioned MHC molecules) that are expressed on virtually all cells in the body and play a key role in the operation of the adaptive immune system. NK cells use germline‐encoded receptors (called NK receptors) that are distinct from the receptors of T‐ and B‐cells and are endowed with the ability to kill cells that express abnormal MHC receptor profiles, as well as other signs of infection.
Cells of the immune system originate in the bone marrow
All cells of the lymphoid and myeloid lineages are derived from a common hematopoietic stem cell progenitor in the bone mar- row (Figure 1.7). These stem cells, which are self‐renewing, give rise to a common lymphoid progenitor as well as a common myeloid progenitor, from which the various types of lymphoid and myeloid cells differentiate (Figure 1.7). This process, called hematopoiesis, is complex and takes place under the guidance of multiple factors within the bone marrow, including stromal cells, the factors they produce and the influence of the extracellular matrix. Indeed, the study of this process is a whole research discipline in itself (hematology) and it has taken many years to unravel the multiplicity of cues that dictate the production of the formed elements of the blood. However, the basic scheme is that the various soluble and membrane‐bound hematopoietic factors influence the differentiation of the various myeloid and lymphoid cell types in a stepwise series of events that involve the switching on of different transcriptional programs at each stage of the hierarchy, such that immature precursor cells are guided towards a variety of specific terminally differentiated cellular phenotypes (monocytes, neutrophils, mast cells, etc.). This process can also be influenced by factors external to the bone marrow (such as cytokines that are produced in the context of immune responses), to ramp up the production of specific cell types according to demand. Make no mistake, this is a large‐scale operation with the average human requiring the production of almost 4 × 1011 leukocytes (400 billion) per day. One of the reasons for this prodigious rate of cell production is that many of the cells of the immune system, particularly the granulocytes (neutrophils, basophils, and eosinophils), have half‐lives of only a day or so. Thus, these cells require practically continuous replacement.
Upon differentiation to specific mature lymphoid and myeloid cell types, the various leukocytes exit the bone marrow and either circulate in the bloodstream until required or until they die (granulocytes), or migrate to the peripheral tissues where they differentiate further under the influence of tissue‐ specific factors (monocytes, mast cells, dendritic cells), or undergo further selection and differentiation in specialized compartments (e.g., T‐cells undergo further maturation and quality control assessment in the thymus, see Chapter 10).
Myeloid cells comprise the majority of cells of the innate immune system
Macrophages and mast cells
Macrophages and mast cells are tissue‐resident cells and are frequently the first dedicated immune cells to detect the presence of a pathogen (Figure 1.8). Both of these cell types have an important role in sensing infection and in amplifying immune responses, through the production of cytokines, chemokines, and other soluble mediators (such as vasoactive amines and lipids) that have effects on the local endothelium and facilitate the migration of other immune cells (such as neutrophils) to the site of an infection through recruitment of the latter from the blood. Mast cells in particular have an important role in promoting vasodilation through production of histamine, which has profound effects on the local vasculature. Macrophages are derived from monocyte precursors that circulate in the blood- stream for a number of hours before exiting the circulation to take up residence in the tissues, where they undergo differentiation into specialized tissue macrophages.
Tissue macrophages have historically been given a variety of names based on their discovery through histological analysis of different tissues. Thus we have Kupffer cells in the liver, microglial cells in the brain, mesangial cells in the kidney, alveolar cells in the lung, osteoclasts in the bone, as well as a number of other macrophage types. Although macrophages do have tissue‐specific functions, all tissue‐resident macrophages are highly phagocytic, can kill ingested microbes, and can generate cytokines and chemokines upon engagement of their PRRs. We will discuss the specific functions of macrophages and mast cells later in this chapter.
Neutrophils and their close relatives, basophils and eosinophils, which are collectively called granulocytes (Figure 1.9), are not tissue‐resident but instead circulate in the bloodstream awaiting signals that permit their entry into the peripheral tissues. Neutrophils, which are also sometimes called polymorphonuclear neutrophils (PMNs), are by far the most numerous of the three cell types, making up almost 97% of the granulocyte population, and are highly phagocytic cells that are adept at hunting down and capturing extracellular bacteria and yeast. Neutrophils arrive very rapidly at the site of an infection, within a matter of a couple of hours after the first signs of infection are detected. Indeed, very impressive swarms of these cells migrate into infected tissues like a shoal of voracious piranha that can boast neutrophil concentrations up to 100‐fold higher than are seen in the blood circulation (Figure 1.10).
Basophils and eosinophils have more specialized roles, coming into their own in response to large parasites such as helminth worms, where they use the constituents of their specialized granules (which contain histamine, DNAases, lipases, peroxidase, proteases, and other cytotoxic proteins, such as major basic protein) to attack and breach the tough outer cuticle of such worms. Because worm parasites are multicellular, they cannot be phagocytosed by macrophages or neutrophils but instead must be attacked with a bombardment of destructive enzymes. This is achieved through release of the granule contents of eosinophils and basophils (a process called degranulation) directly onto the parasite, a process that carries a high risk of collateral damage to host tissues. Basophils and eosinophils are also important sources of cytokines, such as IL‐4, that have very important roles in shaping the nature of adaptive immune responses (discussed later in Chapter 8).
Granulocytes have relatively short half‐lives (amounting to a day or two), most likely related to the powerful destructive enzymes that are contained within their cytoplasmic granules. These are the riot police of the immune system and, being relatively heavy‐handed, are only called into play when there is clear evidence of an infection. Thus, the presence of granulocytes in a tissue is clear evidence that an immune response is underway. Egress of granulocytes from the circulation into tissues is facilitated by changes in the local endothelium lining blood vessels, instigated by vasoactive factors and cytokines/chemokines released by activated tissue macrophages and mast cells, which alter the adhesive properties of the lining of blood vessels closest to the site of infection. The latter changes, which include the upregulation of adhesion molecules on the surface of the local blood vessels, as well as the dilation of these vessels to permit the passage of cells and other blood‐borne molecules more freely into the underlying tissue, facilitate the extravasation of granulocytes from the blood into the tissues.
Dendritic cells (DCs), which were among the first immune cell types to be recognized, are a major conduit between the innate and adaptive arms of the immune system. DCs have characteristic highly elaborated morphology (Figure 1.8), with multiple long cellular processes (dendrites) that enable them to maximize contact with their surroundings. Although most DCs are tissue‐resident cells with phagocytic capacity similar to macrophages, their primary role is not the destruction of microbes, but rather the sampling of the tissue environment through continuous macropinocytosis and phagocytosis of extracellular material. Upon detection and internalization of a PAMP (and its associated microbe) through phagocytosis, DCs undergo an important transition (called DC maturation) from a highly phagocytic but inefficient antigen‐presenting cell into a lowly phagocytic but highly migratory DC that is now equipped to present antigen efficiently to T‐cells within local lymph nodes. We will return to this subject later in this chapter, but the importance of the dendritic cell in the induction of adaptive immunity cannot be overstated.
Lymphoid cells comprise the majority of the cells of the adaptive immune system
T‐ and B‐lymphocytes
Lymphocytes constitute ~20–30% of the leukocyte population and have a rather nondescript appearance (Figure 1.11), which belies their importance within the adaptive immune system.
As mentioned earlier, T‐ and B‐lymphocytes are the central players in the adaptive immune system and have the ability to generate highly specific cell surface receptors, through genetic recombination of a relatively limited number of receptor pre- cursors that are exquisitely specific for particular molecular structures, called antigens. In principle, T‐cell receptors (TCRs) and B‐cell receptors (BCRs, more commonly known as antibodies) can be generated to recognize practically any molecular stucture (i.e., antigen), whether self or nonself derived. However, as we shall see in Chapters 4 and 10, lymphocyte receptors undergo a process of careful inspection after they have been generated to make sure that those that recognize self antigens (or indeed fail to recognize anything useful at all) are weeded out to ensure that the immune response does not become targeted against self (a state called autoimmunity). T‐ and B‐lymphocytes also have the ability to undergo clonal expansion, which enables those lymphocytes that have generated useful (i.e., pathogen‐specific) TCRs and BCRs to undergo rapid amplification, permitting the generation of large numbers of pathogen‐specific T‐ and B‐cells within 5–7 days of the initiation of an immune response. Specific T‐ and B‐cells can also persist in the body for many years (called memory cells), which endows upon them the ability to “remember” previous encounters with particular pathogens and to rapidly mount a highly specific immune response upon a subsequent encounter with the same pathogen.
T‐cells can be further subdivided into three broad subsets: helper (Th), cytotoxic (Tc), and regulatory (Treg) subsets that have roles in helping B‐cells to make antibody (Th), killing virally‐infected cells (Tc,) or policing the actions of other T‐cells (Treg). We will discuss T‐cells and their different subsets extensively in Chapter 8.
Natural killer (NK) cells
NK cells, while also lymphocytes, play a major role within the innate immune system, although these cells also police the presence of special antigen‐presenting molecules (called MHC molecules) that are expressed on virtually all cells in the body and play a key role in the operation of the adaptive immune system. NK cells use germline‐encoded receptors (NK receptors) that are distinct from the receptors of T‐ and B‐cells and are endowed with the ability to kill cells that express abnormal MHC receptor profiles. Viruses often interfere with MHC molecule expression as a strategy to attempt to evade the adaptive immune response, which solicits the attentions of NK cells and can lead to rapid killing of virally infected cells. NK cells also have receptors for a particular antibody class (IgG) and can use this receptor (CD16) to display antibody on their surface and in this way can seek out and kill infected cells, a process called antibody‐dependent cellular cytotoxicity. We will discuss NK cells more extensively later in this chapter.