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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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The recognition and effector mechanisms of adaptive immunity

Clonal selection describes the basic operating principle of the adaptive immune response but not how it defends the body against infection. In the last part of this chapter, we outline the mechanisms by which pathogens are detected by lymphocytes and are eventually destroyed in a successful adaptive immune response. The distinct lifestyles of different pathogens require different response mechanisms, not only to ensure their destruction but also for their detection and recognition (Fig. 1.23). We have already seen that there are two different kinds of antigen receptor: the surface immunoglobulin of B cells, and the smaller antigen receptor of T cells. These surface receptors are adapted to recognize antigen in two different ways: B cells recognize antigen that is present outside the cells of the body, where, for example, most bacteria are found; T cells, by contrast, can detect antigens generated inside infected cells, for example those due to viruses.

Figure 1.23. The major pathogen types confronting the immune system and some of the diseases that they cause.

Figure 1.23

The major pathogen types confronting the immune system and some of the diseases that they cause.

The effector mechanisms that operate to eliminate pathogens in an adaptive immune response are essentially identical to those of innate immunity. Indeed, it seems likely that specific recognition by clonally distributed receptors evolved as a late addition to existing innate effector mechanisms to produce the present-day adaptive immune response. We begin by outlining the effector actions of antibodies, which depend almost entirely on recruiting cells and molecules of the innate immune system.

1-14. Antibodies deal with extracellular forms of pathogens and their toxic products

Antibodies, which were the first specific product of the adaptive immune response to be identified, are found in the fluid component of blood, or plasma, and in extracellular fluids. Because body fluids were once known as humors, immunity mediated by antibodies is known as humoral immunity.

As we have seen in Fig. 1.16, antibodies are Y-shaped molecules whose arms form two identical antigen-binding sites. These are highly variable from one molecule to another, providing the diversity required for specific antigen recognition. The stem of the Y, which defines the class of the antibody and determines its functional properties, takes one of only five major forms, or isotypes. Each of the five antibody classes engages a distinct set of effector mechanisms for disposing of antigen once it is recognized. We shall describe the isotypes and their actions in detail in Chapters 4 and 9.

The simplest and most direct way in which antibodies can protect from pathogens or their toxic products is by binding to them and thereby blocking their access to cells that they might infect or destroy (Fig. 1.24, left panels). This is known as neutralization and is important for protection against bacterial toxins and against pathogens such as viruses, which can thus be prevented from entering cells and replicating.

Figure 1.24. Antibodies can participate in host defense in three main ways.

Figure 1.24

Antibodies can participate in host defense in three main ways. The left panels show antibodies binding to and neutralizing a bacterial toxin, thus preventing it from interacting with host cells and causing pathology. Unbound toxin can react with receptors (more...)

Binding by antibodies, however, is not sufficient on its own to arrest the replication of bacteria that multiply outside cells. In this case, one role of antibody is to enable a phagocytic cell to ingest and destroy the bacterium. This is important for the many bacteria that mare resistant to direct recognition by phagocytes; instead, the phagocytes recognize the constant region of the antibodies coating the bacterium (see Fig. 1.24, middle panels). The coating of pathogens and foreign particles in this way is known as opsonization.

The third function of antibodies is to activate a system of plasma proteins known as complement. The complement system, which we shall discuss in detail in Chapter 2, can also be activated without the help of antibodies on many microbial surfaces, and therefore contributes to innate as well as adaptive immunity. The pores formed by activated complement components directly destroy bacteria, and this is important in a few bacterial infections (see Fig. 1.24, right panels). However, the main function of complement, like that of the antibodies themselves, is to coat the surface of pathogens and enable phagocytes to engulf and destroy bacteria that they would otherwise not recognize. Complement also enhances the bactericidal actions of phagocytes; indeed it is so-called because it ‘complements’ the activities of antibodies.

Antibodies of different isotypes are found in different compartments of the body and differ in the effector mechanisms that they recruit, but all pathogens and particles bound by antibody are eventually delivered to phagocytes for ingestion, degradation, and removal from the body (see Fig. 1.24, bottom panels). The complement system and the phagocytes that antibodies recruit are not themselves antigen-specific; they depend upon antibody molecules to mark the particles as foreign. Antibodies are the sole contribution of B cells to the adaptive immune response. T cells, by contrast, have a variety of effector actions.

1-15. T cells are needed to control intracellular pathogens and to activate B-cell responses to most antigens

Pathogens are accessible to antibodies only in the blood and the extracellular spaces. However, some bacterial pathogens and parasites, and all viruses, replicate inside cells where they cannot be detected by antibodies. The destruction of these invaders is the function of the T lymphocytes, or T cells, which are responsible for the cell-mediated immune responses of adaptive immunity.

Cell-mediated reactions depend on direct interactions between T lymphocytes and cells bearing the antigen that the T cells recognize. The actions of cytotoxic T cells are the most direct. These recognize any of the body's cells that are infected with viruses, which replicate inside cells, using the biosynthetic machinery of the cell itself. The replicating virus eventually kills the cell, releasing new virus particles. Antigens derived from the replicating virus are, however, displayed on the surface of infected cells, where they are recognized by cytotoxic T cells. These cells can then control the infection by killing the infected cell before viral replication is complete (Fig. 1.25). Cytotoxic T cells typically express the molecule CD8 on their cell surfaces.

Figure 1.25. Mechanism of host defense against intracellular infection by viruses.

Figure 1.25

Mechanism of host defense against intracellular infection by viruses. Cells infected by viruses are recognized by specialized T cells called cytotoxic T cells, which kill the infected cells directly. The killing mechanism involves the activation of enzymes (more...)

Other T lymphocytes that activate the cells they recognize are marked by the expression of the cell-surface molecule CD4 instead of CD8. Such T cells are often generically called helper T, or TH cells, but this is a term that we will use for a specific subset of CD4 T cells. CD4 T lymphocytes can be divided into two subsets, which carry out different functions in defending the body, in particular from bacterial infections. The first subset of CD4 T lymphocytes is important in the control of intracellular bacterial infections. Some bacteria grow only in the intracellular membrane-bounded vesicles of macrophages; important examples are Mycobacterium tuberculosis and M. leprae, the pathogens that cause tuberculosis and leprosy. Bacteria phagocytosed by macrophages are usually destroyed in the lysosomes, which contain a variety of enzymes and antimicrobial substances. Intracellular bacteria survive because the vesicles they occupy do not fuse with the lysosomes. These infections can be controlled by a subset of CD4 T cells, known as a TH1 cells, which activate macrophages, inducing the fusion of their lysosomes with the vesicles containing the bacteria and at the same time stimulating other antibacterial mechanisms of the phagocyte (Fig. 1.26). TH1 cells also release cytokines and chemokines that attract macrophages to the site of infection.

Figure 1.26. Mechanism of host defense against intracellular infection by mycobacteria.

Figure 1.26

Mechanism of host defense against intracellular infection by mycobacteria. Mycobacteria are engulfed by macrophages but resist being destroyed by preventing the fusion of the intracellular vesicles in which they reside with the lysosomes containing bactericidal (more...)

T cells destroy intracellular pathogens by killing infected cells and by activating macrophages but they also have a central role in the destruction of extracellular pathogens by activating B cells. This is the specialized role of the second subset of CD4 T cells, called TH2 cells. We shall see in Chapter 9, when we discuss the humoral immune response in detail, that only a few antigens with special properties can activate naive B lymphocytes on their own. Most antigens require an accompanying signal from helper T cells before they can stimulate B cells to proliferate and differentiate into cells secreting antibody (see Fig. 1.21). The ability of T cells to activate B cells was discovered long before it was recognized that a functionally distinct class of T cells activates macrophages, and the term helper T cell was originally coined to describe T cells that activate B cells. Although the designation ‘helper’ was later extended to T cells that activate macrophages (hence the H in TH1), we consider this usage confusing and we will, in the remainder of this book, reserve the term helper T cells for all T cells that activate B cells.

1-16. T cells are specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex

All the effects of T lymphocytes depend upon interactions with target cells containing foreign proteins. Cytotoxic T cells and TH1 cells interact with antigens produced by pathogens that have have infected the target cell or that have been ingested by it. Helper T cells, in contrast, recognize and interact with B cells that have bound and internalized foreign antigen by means of their surface immunoglobulin. In all cases, T cells recognize their targets by detecting peptide fragments derived from the foreign proteins, after these peptides have been captured by specialized molecules in the host cell and displayed by them at the cell surface. The molecules that display peptide antigen to T cells are membrane glycoproteins encoded in a cluster of genes bearing the cumbersome name major histocompatibility complex, abbreviated to MHC.

The human MHC molecules were first discovered as the result of attempts to use skin grafts from donors to repair badly burned pilots and bomb victims during World War II. The patients rejected the grafts, which were recognized as being ‘foreign.’ It was soon appreciated from studies in mice that rejection was due to an immune response, and eventually genetic experiments using inbred strains of mice showed that rapid rejection of skin grafts is caused by differences in a single genetic region. Because they control the compatibility of tissue grafts, these genes became known as ‘histocompatibility genes.’ Later, it was found that several closely linked, and highly polymorphic genes specify histocompatibility, which led to the term major histocompatibility complex. The central role of the MHC in antigen recognition by T cells, which we shall discuss in Chapter 5, was discovered later still, revealing the true physiological function of the proteins encoded by the MHC. This, in turn, led to an explanation for the major effect on tissue compatibility for which they were named. We shall discuss these diverse functions of MHC molecules in Chapters 4, 5, 7, 8, and 13.

1-17. Two major types of T cell recognize peptides bound to proteins of two different classes of MHC molecule

There are two types of MHC molecule, called MHC class I and MHC class II. These differ in several subtle ways but share most of their major structural features. The most important of these is formed by the two outer extracellular domains of the molecule, which combine to create a long cleft in which a single peptide fragment is trapped during the synthesis and assembly of the MHC molecule inside the cell. The MHC molecule bearing its cargo of peptide is then transported to the cell surface, where it displays the peptide to T cells (Fig. 1.27). The antigen receptors of T lymphocytes are specialized to recognize a foreign antigenic peptide fragment bound to an MHC molecule. A T cell with a receptor specific for the complex formed between that particular foreign peptide and MHC molecule can then recognize and respond to the antigen-presenting cell.

Figure 1.27. MHC molecules on the cell surface display peptide fragments of antigens.

Figure 1.27

MHC molecules on the cell surface display peptide fragments of antigens. MHC molecules are membrane proteins whose outer extracellular domains form a cleft in which a peptide fragment is bound. These fragments, which are derived from proteins degraded (more...)

The most important differences between the two classes of MHC molecule lie not in their structure but in the source of the peptides that they trap and carry to the cell surface. MHC class I molecules collect peptides derived from proteins synthesized in the cytosol, and are thus able to display fragments of viral proteins on the cell surface (Fig. 1.28). MHC class II molecules bind peptides derived from proteins in intracellular vesicles, and thus display peptides derived from pathogens living in macrophage vesicles or internalized by phagocytic cells and B cells (Fig. 1.29). We shall see in Chapter 5 exactly how peptides from these different sources are made accessible to the two types of MHC molecule.

Figure 1.28. MHC class I molecules present antigen derived from proteins in the cytosol.

Figure 1.28

MHC class I molecules present antigen derived from proteins in the cytosol. In cells infected with viruses, viral proteins are synthesized in the cytosol. Peptide fragments of viral proteins are transported into the endoplasmic reticulum (ER) where they (more...)

Figure 1.29. MHC class II molecules present antigen originating in intracellular vesicles.

Figure 1.29

MHC class II molecules present antigen originating in intracellular vesicles. Some bacteria infect cells and grow in intracellular vesicles. Peptides derived from such bacteria are bound by MHC class II molecules and transported to the cell surface (top (more...)

Having reached the cell surface with their peptide cargo, the two classes of MHC molecule are recognized by different functional classes of T cell. MHC class I molecules bearing viral peptides are recognized by cytotoxic T cells, which then kill the infected cell (Fig. 1.30); MHC class II molecules bearing peptides derived from pathogens taken up into vesicles are recognized by TH1 or TH2 cells (Fig. 1.31).

Figure 1.30. Cytotoxic T cells recognize antigen presented by MHC class I molecules and kill the cell.

Figure 1.30

Cytotoxic T cells recognize antigen presented by MHC class I molecules and kill the cell. The peptide:MHC class I complex on virus-infected cells is detected by antigen-specific cytotoxic T cells. Cytotoxic T cells are preprogrammed to kill the cells (more...)

Figure 1.31. TH1 and helper T cells recognize antigen presented by MHC class II molecules.

Figure 1.31

TH1 and helper T cells recognize antigen presented by MHC class II molecules. On recognition of their specific antigen on infected macrophages, TH1 cells activate the macrophage, leading to the destruction of the intracellular bacteria (left panel). When (more...)

The antigen-specific activation of these effector T cells is aided by co-receptors that distinguish between the two classes of MHC molecule; cytotoxic cells express the CD8 co-receptor that binds MHC class I molecules, whereas TH1 and TH2 cells express the CD4 co-receptor with specificity for MHC class II molecules. However, even before T cells have encountered the specific foreign antigen that activates them to differentiate into effector cells, they express the appropriate co-receptor to match their receptor specificity. The maturation of T cells into either CD8 or CD4 T cells reflects the testing of T-cell receptor specificity that occurs during development, and the selection of T cells that can receive survival signals from self MHC molecules. Exactly how this selective process works, and how it maximizes the usefulness of the T cell repertoire is a central question in immunology and is a major topic of Chapter 7.

On recognizing their targets, the three types of T cell are stimulated to release different sets of effector molecules. These can directly affect their target cells or help to recruit other effector cells in ways we shall discuss in Chapter 8. These effector molecules include many cytokines, which have a crucial role in the clonal expansion of lymphocytes as well as in innate immune responses and in the effector actions of most immune cells; thus, understanding the actions of cytokines is central to understanding the various behaviors of the immune system.

1-18. Defects in the immune system result in increased susceptibility to infection

We tend to take for granted the ability of our immune systems to free our bodies of infection and prevent its recurrence. In some people, however, parts of the immune system fail. In the most severe of these immunodeficiency diseases, adaptive immunity is completely absent, and death occurs in infancy from overwhelming infection unless heroic measures are taken. Other less catastrophic failures lead to recurrent infections with particular types of pathogen, depending on the particular deficiency. Much has been learned about the functions of the different components of the human immune system through the study of these immunodeficiencies.

More than twenty-five years ago, a devastating form of immunodeficiency appeared, the acquired immune deficiency syndrome, or AIDS, which is itself caused by an infectious agent. This disease destroys the T cells that activate macrophages, leading to infections caused by intracellular bacteria and other pathogens normally controlled by these T cells. Such infections are the major cause of death from this increasingly prevalent immunodeficiency disease, which is discussed fully in Chapter 11 together with inherited immunodeficiencies.

AIDS is caused by a virus, the human immunodeficiency virus, or HIV, that has evolved several strategies by which it not only evades but also subverts the protective mechanisms of the adaptive immune response. Such strategies are typical of many successful pathogens and we shall examine a variety of them in Chapter 11. The conquest of many of the world's leading diseases, including malaria and diarrheal diseases (the leading killers of children) as well as the more recent threat from AIDS, depends upon a better understanding of the pathogens that cause them and their interactions with the cells of the immune system.

1-19. Understanding adaptive immune responses is important for the control of allergies, autoimmune disease, and organ graft rejection

Many medically important diseases are associated with a normal immune response directed against an inappropriate antigen, often in the absence of infectious disease. Immune responses directed at noninfectious antigens occur in allergy, where the antigen is an innocuous foreign substance, in autoimmune disease, where the response is to a self antigen, and in graft rejection, where the antigen is borne by a transplanted foreign cell. What we call a successful immune response or a failure, and whether the response is considered harmful or beneficial to the host, depends not on the response itself but rather on the nature of the antigen (Fig. 1.32).

Figure 1.32. Immune responses can be beneficial or harmful depending on the nature of the antigen.

Figure 1.32

Immune responses can be beneficial or harmful depending on the nature of the antigen. Beneficial responses are shown in white, harmful responses in shaded boxes. Where the response is beneficial, its absence is harmful.

Allergic diseases, which include asthma, are an increasingly common cause of disability in the developed world, and many other important diseases are now recognized as autoimmune. An autoimmune response directed against pancreatic β cells is the leading cause of diabetes in the young. In allergies and autoimmune diseases, the powerful protective mechanisms of the adaptive immune response cause serious damage to the patient.

Immune responses to harmless antigens, to body tissues, or to organ grafts are, like all other immune responses, highly specific. At present, the usual way to treat these responses is with immunosuppressive drugs, which inhibit all immune responses, desirable or undesirable. If it were possible to suppress only those lymphocyte clones responsible for the unwanted response, the disease could be cured or the grafted organ protected without impeding protective immune responses. There is hope that this dream of antigenspecific immunoregulation to control unwanted immune responses could become a reality, since antigen-specific suppression of immune responses can be induced experimentally, although the molecular basis of this suppression is not fully understood. We shall see in Chapter 10 how the mechanisms of immune regulation are beginning to emerge from a better understanding of the functional subsets of lymphocytes and the cytokines that control them, and we shall discuss the present state of understanding of allergies, autoimmune disease, graft rejection, and immunosuppressive drugs in Chapters 12, 13, and 14.

1-20. Vaccination is the most effective means of controlling infectious diseases

Although the specific suppression of immune responses must await advances in basic research on immune regulation and its application, the deliberate stimulation of an immune response by immunization, or vaccination, has achieved many successes in the two centuries since Jenner's pioneering experiment.

Mass immunization programs have led to the virtual eradication of several diseases that used to be associated with significant morbidity (illness) and mortality (Fig. 1.33). Immunization is considered so safe and so important that most states in the United States require children to be immunized against up to seven common childhood diseases. Impressive as these accomplishments are, there are still many diseases for which we lack effective vaccines. And even where vaccines for diseases such as measles or polio can be used effectively in developed countries, technical and economic problems can prevent their widespread use in developing countries, where mortality from these diseases is still high. The tools of modern immunology and molecular biology are being applied to develop new vaccines and improve old ones, and we shall discuss these advances in Chapter 14. The prospect of controlling these important diseases is tremendously exciting. The guarantee of good health is a critical step toward population control and economic development. At a cost of pennies per person, great hardship and suffering can be alleviated.

Figure 1.33. Successful vaccination campaigns.

Figure 1.33

Successful vaccination campaigns. Diphtheria, polio, and measles and its consequences have been virtually eliminated in the United States, as shown in these three graphs. SSPE stands for subacute sclerosing panencephalitis, a brain disease that is a late (more...)

Summary

Lymphocytes have two distinct recognition systems specialized for detection of extracellular and intracellular pathogens. B cells have cell-surface immunoglobulin molecules as receptors for antigen and, upon activation, secrete the immunoglobulin as soluble antibody that provides defense against pathogens in the extracellular spaces of the body. T cells have receptors that recognize peptide fragments of intracellular pathogens transported to the cell surface by the glycoproteins of the major histocompatibility complex (MHC). Two classes of MHC molecule transport peptides from different intracellular compartments to present them to distinct types of effector T cell: cytotoxic T cells that kill infected target cells, and TH1 cells and helper T cells that mainly activate macrophages and B cells, respectively. Thus, T cells are crucially important for both the humoral and cell-mediated responses of adaptive immunity. The adaptive immune response seems to have engrafted specific antigen recognition by highly diversified receptors onto innate defense systems, which have a central role in the effector actions of both B and T lymphocytes. The vital role of adaptive immunity in fighting infection is illustrated by the immunodeficiency diseases and the problems caused by pathogens that succeed in evading or subverting an adaptive immune response. The antigen-specific suppression of adaptive immune responses is the goal of treatment for important human diseases involving inappropriate activation of lymphocytes, whereas the specific stimulation of an adaptive immune response is the basis of successful vaccination.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27124