The First Line Of Body Defence

Our body has evolved three kinds of defence strategy against infectious agents, some of which (i.e. viruses) have been associated with the development of human cancers (Marieb and Hoehn, 2007). All viruses, and some bacteria, can live and multiply inside the host cells. These are called intracellular pathogens. In contrast, most bacteria and larger parasites live and multiply outside the cells, in the body tissues and fluids. These are called extracelluar pathogens. The first line of defence against infectious agents is non-immunological and involves a number of physical and chemical barriers, also called external defences. An unbroken skin is the most important protection for the body, acting as a physical barrier to stop invasion by foreign micro-organisms and other substances. The skin also has secretions, such as acidic sweat and fatty acids from oil glands, which can destroy or inhibit bacterial growth on its surface. In addition, there is a normal population of microflora which can colonize the surface of the skin and inhibit growth of potential pathogens by competing for the available space and nutrients at the site (Wood, 2006).

Mucous membranes at the openings to the digestive, respiratory, urinary and reproductive tracts also protect the body from invasion by foreign micro-organisms. Mucous traps bacteria and other foreign substances and can be expelled from the body. The urinary and reproductive tracts are free from micro-organisms under normal circumstances. Regular urination and secretion of mucous flushes any micro-organisms towards the outside of the body, although some microflora and opportunistic pathogens can enter from the surrounding areas. Movement of the gut contents and expulsion of the faeces helps to remove unwanted bacteria.

Other physical and chemical barriers include the anti-microbial enzyme lysozyme in perspiration, tears, saliva and nasal secretions, and the acidity of gastric juice in the stomach (Wood, 2006; Marieb and Hoehn, 2007). Such physical and chemical barriers are often sufficient in preventing the infection and disease caused by pathogens (Figure 8.1).

The immune system is a complex network of immune cells, cytokines, lymphoid tissues and organs that work together to eliminate infectious agents and other antigens (Tables 8.1-8.3). When infectious agents are not stopped by the physical and chemical barriers described above, they enter the body through the skin or mucous membranes. This initiates the first line of immunological defence mechanism, called the innate, non-specific or natural immune response. If the pathogens are not eliminated by the innate immune response then disease ensues and the adaptive, specific or acquired immune response activates, allowing the body to recover (Figure 8.1). The two important differences between the innate and adaptive immune responses are that (i) the latter is highly specific for a particular pathogen/antigen and (ii) the latter response improves with each subsequent exposure to the same antigen. However, as we shall see later on, the innate and adaptive immune responses work together at several levels (e.g. by releasing growth promoting cytokines) in order to destroy invading antigens.

Table 8.1 Cells of the immune system

Cell

Function

Phagocytes

Antigen presenting cells

Natural killer cells

B-lymphocytes

Plasma cells Cytotoxic T-cell (killer T-cell, Tc)

Helper T-cell (THi T4) Memory T-cells

Suppressor T-cells

Ingest and digest foreign antigens/pathogens by the process of phagocytosis (e.g. macrophages, neutrophils). Process and present antigens to T-lymphocytes (e.g. dendritic cells, macrophages, B-cells). Kill tumour cells and some viral infected cells. Are lymphocytes but, unlike B- and T-cells, lack specificity and memory.

Express antibodies on their cell surface that can bind to antigens and differentiate to antibody-producing plasma cells.

The antibody secreting form of B-lymphocytes. Subset of T-lymphocytes (CD8+) that recognize cells expressing foreign antigens in association with MHC-I molecules and kill by releasing cytokines perforin and lymphotoxin. Release other cytokines that stimulate phagocytosis and inhibit viral replication.

Subset of T-lymphocytes (CD4+) that produce cytokines to stimulate both antibody and cell-mediated immune response.

Develop after the first exposure to a particular antigen. Remain in circulation and recognize the original antigen years after the first exposure, and respond more rapidly and efficiently in second and subsequent exposures. Down-regulate the immune responses.

Table 8.2 Important cytokines of the immune system

Cytokine

Function

Interleukin IL-1

IL-2

IL-4

IL-5

IL-6

IL-8

IL-10

IL-12

IL-15 IL-18

Interferons (IFN)

Tumour necrosis factor (TNF) Lymphotoxin (LT)

Perforin

Granzymes

Transforming growth factor (TGF(3)

Mainly from macrophages, contributing to fever, and T-cell and macrophage activation.

Secreted by helper T-cells. Co-stimulate proliferation of helper T-cells, cytotoxic T-cells and B-cells. Activate NK cells. Produced by T- and B-cells and macrophages. Involved in activation of B-cells, differentiation of TH2-cells and suppression of TH1-cells Mainly from helper T-cells and mast cells. Principal action in activation and chemoattraction of eosinophils.

Mainly from macrophages, endothelial cells and T-cells. Target synthesis of acute phase proteins in the liver. Induce proliferation of antibody producing cells.

Macrophage derived chemoattractant for immune system cells and phagocytes to site of inflammation.

Secreted by T- and B-cells and macrophages. Involved in suppression of macrophage function and TH1-cells. Activate B-cells. Produced mainly by dendritic cells and macrophages. Mainly involved in differentiation of TH1-cells and activation of NK cells and T-cells.

Mainly from macrophages. Induce proliferation of NK cells and T-cells.

Mainly from macrophages. Enhance NK cytotoxicity and IFN synthesis by T-cells.

Produced by macrophages, lymphocytes and NK cells. Major macrophage activators. Activate NK cells. Enhance AMI and CMI responses. Antiviral activity.

Mainly from macrophages and helper T-cells. Cytotoxic to tumour cells. Enhance activity of phagocytic cells.

Secreted by cytotoxic T-cells. Kills cells by activating cell's own caspase enzymes, which induce an endonuclease to degrade the cell's DNA (apoptosis).

Secreted by cytotoxic T-cells and NK cells. Polymerizes to form tubular structures which perforate the lipid bilayer of the target cells, leading to osmotic lysis.

Secreted by cytotoxic T-cells and NK cells. Pass through perforin pores and induce apoptosis from within the target cell cytoplasm. Produced by T-cells and monocytes. Inhibits T- and B-cell proliferation and NK cell activity.

INNATE (NATURAL, NON-SPECIFIC) IMMUNE RESPONSE

The innate immune response is present at birth and is mediated by a complex sequence of cellular and molecular events, including phagocytosis, inflammation,

Table 8.3 Important recognition moieties of the immune system Function

Antibodies

Complement MHC

CD4 CD8

Co-stimulatory molecules Antigens/Epitopes

Vaccine

Chemotaxis

Produced by plasma cells differentiated from B-lymphocytes. Enhance phagocytosis by opsonization. Neutralize antigens and activate complement. The Ag/Ab complex can bind to effector cells such as NK cells and macrophages, targeting the antigen for destruction by ADCC.

Over 20 serum glycoproteins that, once activated, lead to cell lysis, inflammation and opsonization.

Major Histocompatibility Complex molecules bind and 'present' antigenic peptides on the surfaces of cells for recognition by the antigen-specific T-cell receptor (TCR). Two classes: MHC-I on all nucleated cells, MHC-II on antigen presenting immune cells. Molecules expressed on helper T-cells bind antigenic peptides presented by MHC-II.

Molecules expressed on cytotoxic T-cells bind antigenic peptides presented by MHC-I.

Adhesion molecules/cytokines which provide the second signal for T-cell activation.

Substances that provoke immune responses (e.g. bacteria, pollen, transplanted tissues) are called antigens. Each antigen may have several components called epitopes, and each epitope provokes the production of a specific antibody or stimulates a specific T-lymphocyte. (Antigen = antibody generator.) A modified form of the original antigen that is used in vaccination in order to stimulate the production of memory B-cells and memory T-cells without causing the disease. Antigenic preparations that are used in educating the immune system.

The migration of a cell to the site of infection in response to a chemical stimulus (e.g. complement components), causing accumulation of leukocytes in inflamed tissues.

complement activation and natural killer cell activation. In contrast to the adaptive immune response, which improves with each successive exposure to the same antigen, the innate immune response does not change following repeated exposures. Some of the main components of the innate immune system, also called innate immunity, are briefly described here.

Phagocytosis and Phagocytic Cells

Phagocytosis is a multistep process by which phagocytic cells engulf and destroy infectious agents. Like other types of white blood cell, phagocytic cells are derived from a common pluripotent stem cell in the red bone marrow. Phagocytes are attracted to the site of infection by a process called chemotaxis. Examples of chemotatic factors include microbial products, damaged leukocytes or tissue cells, complement components (e.g. C5a) and certain cytokines. The process continues with adherence of the phagocyte's plasma membrane to the surface of the microorganism. This occurs more readily after opsonization, where the microbe is coated by complement proteins or antibody molecules (see below). By extending the plasma membrane projections, called pseudopodia, phagocytic cells engulf the pathogen, forming a phagocytic vacuole (i.e. phagosome), and fuse it with a lysosome. The phagocytosed pathogen can then be digested by the appropriate digestive enzymes (e.g. lysozyme) and bactericidal chemicals. The indigestible products are ejected from the cell by exocytosis. Examples of phagocytic cells include neutrophils, monocytes and macrophages.

Neutrophils, which are the most abundant type of white blood cell, respond very rapidly to infection, are relatively short-lived (1-5 days) and can only phagocytose small pathogens, such as viruses and bacteria. In response to infection, bone marrow can produce between 1 and 2x10n neutrophils per day. The number of neutrophils in the circulation does not alter with age (Lords et al., 2001). In contrast to neutrophils, macrophages ('big eaters') in the tissues are derived from monocytes in the blood, respond more slowly to chemotactic stimuli, but are more efficient in the phagocytosis of the remaining living and dead pathogens. Macrophages can live for months or years and kill infectious agents by several mechanisms; for example, the secretion of a wide range of molecules such as anti-viral interferon or anti-bacterial lysozyme and the generation of oxygen radicals, nitric oxide and chlorine-containing products (Wood, 2006). Macrophages may be fixed in a particular tissue (e.g. kupffer cells in the liver, microglia in the brain) or they may move throughout the body in search of pathogens (these are termed 'wandering macrophages'). The activated macrophages produce a number of cytokines (e.g. Interleukin-1 (IL-1), Interleukin-8 (IL-8), TNFa and IFNa) that stimulate an inflammatory response and bring an additional army of immune cells and molecules to the site of infection (Table 8.2). This additional array of cells and molecules can more effectively destroy the invading pathogens.

Macrophages are also very important in the activation of adaptive (specific) immune responses against invading pathogens, by presenting a fragment of processed antigen on their cell surface in association with class II MHC molecules to CD4+ T-lymphocytes (see later). This results in the activation of CD4+ helper T-lymphocytes, which in turn can stimulate both the antibody-mediated and cellmediated immune responses against infectious agents (Figure 8.2, and see below).

Inflammation

Damage to the body's tissues by microbial infection, physical agents like heat or sharp objects, and chemical agents such as acid burns, leads to a complex series of non-specific physiological responses, called inflammation. The main aims are to

CD8+ cytotoxic T-cells induce CMI and are particularly effective against intracellular antigen (e.g. viruses, mycobacteria) and cancer cells stimulate phagocytosis and ADCC

Antibodies induce AMI and are particularly effective against extracellular antigens (e,g. bacteria, cell surface tumour antigens)

CD8+ cytotoxic T-cells induce CMI and are particularly effective against intracellular antigen (e.g. viruses, mycobacteria) and cancer cells stimulate phagocytosis and ADCC

Antibodies induce AMI and are particularly effective against extracellular antigens (e,g. bacteria, cell surface tumour antigens)

Figure 8.2 The central role played by CD4+ helper T-cells in all types of immune responses. The CD4+ T-cells stimulated by antigen differentiate into CD4+ helper T-cell subsets Th1 and TH2. The cytokines released by TH1-cells in turn help the cell-mediated immune response by increasing the population of antigen specific CD8+ cytotoxic T-cells and by activating macrophages, which are important in the innate immune response. The cytokines released by TH2-cells can aid the antibody-mediated immune response by increasing the population of antigen specific B-cells and plasma cells. The production of cytokines by macrophages can also activate the proliferation and differentiation of helper T-cells.

localize the infection and prevent the spread of any microbial invaders, to recruit additional immune cells (e.g. neutrophils and monocytes) and molecules from the blood to the infected area, to neutralize toxins and to repair and replace damaged tissue. The tissue macrophages can stimulate inflammation further by releasing cytokines (IL-1, IL-8 and TNFa), which cause vasodilatation, increase vascular permeability and are chemotatic for neutrophils and monocytes (Wood, 2006). Vasodilation increases blood flow to the damaged area, leading to redness and heat at the site of injury. This allows an increase in the concentration of complement and other chemotactic factors at the infected areas, which ultimately enhances phagocyte migration and phagocytosis at the site of injury. Tissue repair can occur once all harmful substances and damage have been removed.

Complement Activation

The complement system contains a cascade of inactive proteins in the blood, which can be activated following the binding of an antibody to bacteria and other foreign cells, or by an alternative pathway involving the presence of bacterial capsular polysaccharides. Once activated, the complement system generates a number of biologically active proteins that enhance inflammation and phagocytosis and promote cell lysis. For example, the complement proteins C3a, C4a and C5a enhance inflammatory reactions by stimulating dilation of arteries, releasing histamine from mast cells and basophils and attracting neutrophils by chemo-taxis. Other members of the complement system promote cell lysis by forming the membrane attack complex (C5b-C6, C7, C8 and C9). The complement fragment C3b is an important opsonin and can coat the cell surface of pathogens. Phagocytic cells such as macrophages, monocytes and neutrophils all have C3b receptors on their surface. Such receptors can help the elimination of the pathogens by promoting phagocytosis (Rabson, Roitt and Delves, 2005; Wood, 2006; Marieb and Hoehn, 2007).

Natural Killer (NK) Cells

NK cells are a distinct subpopulation of lymphocytes which play an important role in the natural immune response by mediating cytotoxic effects in the target cells and by releasing cytokines such as IFN7 and TNFa (Tables 8.1 and 8.2). Unlike B- or T-lymphocytes, NK cells lack specificity and memory but can induce spontaneous lysis of cells infected with viruses and of various tumour cells by secretion of perforin and other lytic enzymes (Solana and Mariani, 2000; Rabson, Roitt and Delves, 2005). As described in Chapter 10, NK cells, in addition to their direct cytotoxic killing, can induce an antibody-dependent cell-mediated cytotoxicity (ADCC) in target cells by binding to the Fc portion of the antibody (Gorczynsky and Stanley, 2006). For example, organisms such as protozoa or helminthes, which are too large to be engulfed by phagocytic cells, can be coated with antibodies. When the antigen binding sites of the antibody (e.g. human IgG1 and IgG3 antibodies) have bound to such antigens, the Fc portions of the antibodies are free and can bind to the Fc receptor on NK cells, directing cell killing by ADCC (Figure 8.2). In addition to NK cells, macrophages, neutrophils and eosinophils also have Fc receptors that can bind to the Fc portion of the antibody molecule and direct cell killing by ADCC.

While the absolute number of NK cells increases with age, their cytotoxic capacity decreases, and this is a characteristic feature of immunosenescence (Malaguarnera et al., 2001; Rabson, Roitt and Delves, 2005). For example, NK cells from old donors have been shown to respond less efficiently to the mitogenic cytokine IL-2, which can result in decreased proliferation of NK cells and decreased production of IFN by NK cells. This may ultimately lead to a decreased cytotoxic response by NK cells against the target antigen on the infectious agent or tumour cell (Solana and Mariani, 2000).

Cytokines

Both natural and adaptive immunity are coordinated by about 60 cytokines (Tagawa, 2000; Sprent and Surh, 2003; Abbass and Lichtman, 2006). These are small protein hormones that can stimulate or inhibit many normal cell functions but are less specific and more localized than endocrine hormones (Table 8.2). Cytokines can be divided into several families, including interleukins, interferons, tumour necrosis factors, colony stimulating factors and chemokines, which regulate the migration of cells between and within tissues. For example, there are around 22 different interleukins (ILs), numbered IL-1 to IL-22. Of these, IL-1 is secreted by macrophages and monocytes and can stimulate an inflammatory response and activate lymphocytes (Table 8.2 and Figure 8.2). IL-2 is produced by T-helper lymphocytes and stimulates the proliferation of T-helper cells, cytotoxic T-cells and B-lymphocytes, and activates NK cells. On the other hand, IL-10 and transforming growth factor-^ (TGFP) are immunosup-pressants and inhibit the cytotoxic response of the immune system (T-cells and macrophages) against the antigens from tumours and infectious agents (Table 8.2; Levings et al., 2002; Rabson, Roitt and Delves, 2005). Therefore, drugs that block the immunosuppressive action of IL-10 and TGF on the immune system may play an important role in the treatment of human cancers, while those that stimulate their function are useful in suppressing pathological immune responses such as those in autoimmune diseases, allergies and transplantation rejection.

Some of the cytokines are listed in Table 8.2 along with their functions.

ADAPTIVE (ACQUIRED, SPECIFIC) IMMUNE RESPONSE

In many situations, the non-specific immune responses described above (phagocytosis, natural killer cell activation, inflammation), which we are born with and occur in the first few hours of infection, may be sufficient in overcoming the pathogens. If not, disease can ensue and the body must recover by the activation of adaptive immune responses against the invading pathogens (Figure 8.1). There are two types of adaptive immune response, namely AMI and CMI.

The most important cells in providing adaptive immune responses are lymphocytes, which make up between 25% and 35% of white blood cells; their total number in a healthy individual is close to one billion (1012) (Marieb and Hoehn, 2007). Two major types of lymphocyte, called B-cells and T-cells, are present in the blood in a 1:5 ratio. B-cells develop into mature immunocompetent cells in the red bone marrow and each B-cell expresses an antigen receptor (i.e. antibody) of a single specificity on its cell surface. B-cells are responsible for the antibody-mediated immune response (Figure 8.2). In antibody-mediated immunity, the binding of antigen to antigen receptor (i.e. antibody) on B-cells can result in the activation and differentiation of B-cells into antibody-secreting plasma cells. However, ensuring full activation and differentiation of B-cells into plasma cells in response to most antigens, and the antibody class switching (e.g. from low affinity IgM subclass into high affinity IgG subclass), requires a co-stimulator signal, provided by the interaction of B-cells with CD4+ helper T-cells (i.e. T-cells expressing CD4 antigen, see below) (Rabson, Roitt and Delves, 2005).

The binding of CD154 molecules on the CD4+ T-cell to CD40 molecules on the B-cell, together with production of cytokines such as IL-4 and IL-5 by CD4+ helper T-cells, can result in the full activation of B-cells and their differentiation into antibody-producing plasma cells (Figure 8.2) (Abbass and Lichtman, 2006). Each plasma cell then secretes up to 2000 antibodies per second against the original antigen and this process can continue for about 4-5 days. The antibody production by plasma cells can be increased by cytokine IL-6. The secreted antibodies then circulate in the blood and lymphatic system, and bind to the original antigens, marking them for elimination by several mechanisms, including activation of the complement system, promotion of phagocytosis via opsonization and mediation of ADCC with effector cells such as macrophages, NK cells and neutrophils (Figure 8.2).

In contrast to the AMI, a CMI against invading pathogen is mediated by T-cells. Whereas B-cells complete their maturation in bone marrow, T-lymphocytes develop from pre-T-cells in the bone marrow and mature in the thymus into CD4+ or CD8+ expressing T-cells (Figure 8.2). In CMI, CD8+ T-cells, which recognize the target antigen, proliferate and differentiate into CD8+ cytotoxic T-cells (Tc), which kill the target antigens by delivering a lethal dose of the cytokines lympho-toxin and perforin or by directing apoptosis (Figure 8.2) (Marieb and Hoehn, 2007). T-cells expressing CD4+ antigen are called helper T-cells (TH0) and the binding of antigens to such cells results in their proliferation and differentiation into two CD4+ helper T-cell subsets, TH1 and TH2. The TH1-cells produce cytokines such as IL-2 and IFN7, which stimulate cell-mediated immune responses against intracellular pathogens and tumour cells. In contrast, TH2-cells produce cytokines IL-4, IL-5 and IL-6, which play a central role in regulating the antibody-mediated immune response against extracellular antigens and pathogens (Figure 8.2) (Rabson, Roitt and Delves, 2005). The production of cytokines by TH1-cells can further help the elimination of the target antigen by macrophages of the innate immune system (Figure 8.2). For this reason, CD4+ helper T-cells are viewed as the backbone of the immune system. Their crucial role has been highlighted in patients with AIDS, where the helper T-cells are targeted by the virus (Altfeld and Rosenberg, 2000). In a normal uninfected individual, the number of CD4+ T-cells is between 800 and 1200 cells per cubic millimetre of blood. When the number of CD4+ T-cells falls below 200/mm3 of blood towards the final stage of HIV infection, patients become particularly susceptible to opportunistic infections by microbes that do not usually cause disease in healthy individuals, as well as to cancers such as Kaposi's sarcoma and lymphomas. Indeed, AIDS cases are part of the evidence supporting both the idea that immunosuppression can increase the incidence of cancer, and the immune surveillance concept (Scadden, 2003; and see below).

In addition to CD8+ cytotoxic T-cells and CD4+ helper T-cells, there are other populations of T-lymphocytes, which inhibit the immune response by releasing inhibitor cytokines. These cells are called suppressor T-cells (Ts) (McHugh and Shevach, 2002; Marieb and Hoehn, 2007).

MHC Molecules and Antigen Recognition and Processing in Cell-Mediated Immunity

As described above, T-lymphocytes are responsible for cell-mediated immunity against foreign antigens. The aim of the majority of cancer vaccines under investigation is to develop antigen-specific T-cell-mediated immune responses against tumour antigens.

However, as with B-cells, successful activation of different T-cells requires the presence of two signals, namely a recognition signal and a co-stimulatory signal. The first signal is recognition of the antigen by the antigen receptors on the surface of the T-cells, called T-cell receptors (TCR), which results in the movement of the T-cells from a resting phase of the cell cycle (G0) to G: phase. However, unlike some B-cells, which can bind directly to an antigen with their unique antigen receptors (i.e. antibodies), the TCRs on both CD4+ and CD8+ T-cells can only recognize a fragment of an antigen that has been processed and presented in association with a unique cell surface self-antigen, called the major histocompatibility complex (MHC) antigen (Rabson, Roitt and Delves, 2005). There are two major types of self-MHC molecule, which are also called human leukocyte antigens (HLAs). MHC class I molecules are found on all body cells except red blood cells, and present the intracellular antigens to the TCRs on CD8+ T-cells. In contrast, class II MHC molecules are present only on the surface of antigen-presenting cells (APCs) such as macrophages, B-lymphocytes and dendritic cells, and are important in the presentation of exogenous antigens to the T-cell receptors on CD4+ helper T-cells (Figure 8.3).

Following the binding of the MHC-antigen fragment complex to the TCR, the T-cells become activated only if they receive a second signal, called a co-stimulatory signal. This second signal has been shown to be essential for full activation of T-cells. The majority of co-stimulatory molecules are cell adhesion molecules, which allow the two cells to adhere to one another for a longer period and result in sustained proliferation and differentiation of T-cells (Figure 8.3). For example, activation and differentiation of CD4+ T-cells into helper T-cells requires the binding of CD28 molecules on CD4+ T-cells to CD80/CD86 molecules present on antigen-presenting cells. This in turn results in the production of IL-2, IL-2 receptor expression and cell cycle progression and proliferation of activated T-cells. In contrast to CD4+ helper T-cells, the full activation of cytotoxic T-cells against the target cells is promoted by the binding of the CD2 molecule on CD8+ T-cells to the CD58 molecule on target cells, and by the interaction of lymphocyte functional antigen-1 (LFA-1) on the T-cell with intercellular adhesion molecule-1 (ICAM-1) on the target cells. Recognition of the antigens by the antigen receptors on the lymphocyte in the absence of co-stimulatory signals results in the production of no cytokines, a state of immunological unresponsiveness called anergy, or even in increased programmed cell death (Frauwirth and Thompson, 2002; Rabson, Roitt and Delves, 2005). Indeed, deficiencies or abnormalities in some of these components can help tumours cells to escape recognition and destruction by T-cells (see below).

Degraded antigen fragments

Co-stimulatory molecules

.Antigen uptake iff by APC

Shed tumour antigen or extracellular pathogen

Antigen presenting cell (APC) (e.g. macrophage, dendritic cell)

Degradation of intracellular antigen

Tumour cell, APC or a cell infected by viruses

Degraded antigen fragments

Co-stimulatory molecules

.Antigen uptake iff by APC

Shed tumour antigen or extracellular pathogen

Activated CD4+ T-cells (TH) secrete cytokines that amplify both CMI and AMI (e.g. IL-2 and IL-4). Some remain as long lived memory TH-cells

Class-II MHC

Processed antigen

CD4+ T-cell receptor

Class-II MHC

Processed antigen

Co-stimulatory molecules

CD4+ T-cell receptor

Class I MHC

Processed antigen

CD8+ T-cell receptor

Activated CD4+ T-cells (TH) secrete cytokines that amplify both CMI and AMI (e.g. IL-2 and IL-4). Some remain as long lived memory TH-cells

Co-stimulatory molecules

Degradation of intracellular antigen

Activated CD8+ T-cells proliferate & differentiate into cytotoxic T-cells (TC) and kill target cells by inducing apoptosis or by delivering a lethal dose of lymphotoxin & perforin. Some remain as long-lived memory TC-cells

Class I MHC

Processed antigen

CD8+ T-cell receptor

Figure 8.3 Successful activation of antigen-specific T-cell responses requires two signals. (A) CD4+ helper T-cells are only activated when the T-cell receptor recognizes an antigen fragment, from exogenous antigens, in association with class II MHC molecule (signal 1), and receives a co-stimulatory signal by binding the CD28 molecule on T-cells to the CD80/CD86 molecule on the antigen-presenting cell (signal 2). (B) CD8+ T-cells are only activated when the T-cell receptor recognizes an antigen fragment, from endogenous antigens, in association with class I MHC molecule (signal 1), and receives a co-stimulatory signal via interaction between other cell surface (adhesion) molecules (signal 2). Recognition without the second signal results in anergy (a prolonged state of inactivity) and programmed cell death.

Activated CD8+ T-cells proliferate & differentiate into cytotoxic T-cells (TC) and kill target cells by inducing apoptosis or by delivering a lethal dose of lymphotoxin & perforin. Some remain as long-lived memory TC-cells

Figure 8.3 Successful activation of antigen-specific T-cell responses requires two signals. (A) CD4+ helper T-cells are only activated when the T-cell receptor recognizes an antigen fragment, from exogenous antigens, in association with class II MHC molecule (signal 1), and receives a co-stimulatory signal by binding the CD28 molecule on T-cells to the CD80/CD86 molecule on the antigen-presenting cell (signal 2). (B) CD8+ T-cells are only activated when the T-cell receptor recognizes an antigen fragment, from endogenous antigens, in association with class I MHC molecule (signal 1), and receives a co-stimulatory signal via interaction between other cell surface (adhesion) molecules (signal 2). Recognition without the second signal results in anergy (a prolonged state of inactivity) and programmed cell death.

Adaptive Immune System, Immunological Memory and Vaccination

Two characteristic features of the adaptive immune response are specificity for a particular antigen and immunological memory. Once the invading pathogens are destroyed by the adaptive immune response, some of the activated B-lymphocytes and T-lymphocytes differentiate into thousands of memory B-cells and memory T-cells. When the body encounters the same pathogen for a second time, these memory cells, which can remain in circulation decades after the first exposure, increase their population so rapidly that the pathogens are destroyed before the body develops any signs of disease (Sprent, 2003; Marieb and Hoehn, 2007).

The development of memory B-cells and memory T-cells against the antigen on the infectious agent or cancer cell is the rationale for successful immunization by vaccination (Wood, 2006). The vaccination of children against infectious agents is estimated to save the lives of 3 million children a year, by helping the body to prevent primary infection (Andre, 2003). The development of vaccines against cancer is more challenging as, unlike vaccines against infectious diseases, cancer vaccines are developed for the treatment of a disease that is already present in the body, and not merely for its prevention (Berd, 1998; Moingeon, 2001; Davidson, Kitchener and Stern, 2002).

In summary, the full activation of the immune system and successful destruction of any foreign antigens, cells and infectious agents by adaptive immune responses requires cooperation between immune cells of adaptive and innate immunity, the production of cytokines by such cells and the presence of co-stimulatory signals, which are essential for activation and proliferation of antigen-specific B-cells and T-cells. Abnormalities in any one of the above components can lead to a state of immunological unresponsiveness against the target antigen.

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