14 Chapter 1:Basic Concepts in Immunology on the tissues of the body and attacking them?Ray Owen had shown in the ponsive,or tolerant,to one another's tissues:they did not r an immune O nologicalytoleant6eeag sedhaedeveiopt 9999999 portillpp re h tion.He hassince been provedg worked out.as we shall see when we discuss the development of lymphocy orincinle in 9999999 Clonal selection of lymphocytes is the single most important p adaptive immunity.Its four basic postulates are listed in Fig.1.13.The last problems posed by the onal selection theory- ed i ,197 advances in molecular biology made it possible to clone the genes encoding antibody molecules. Pool of mature naive lymphocytes 1-11 The structure of the antibody molecule illustrates the central puzzle 999 of adaptive immunity. As discussed abov od fo of the B cell's a foreign antiger ebre rec d an that antibody mole les are composed of two distinct regions One is CO O○OOO infinite variety of different amino acid sequences,forming subtly differen ed in E depicted as aY-shaped molecule.The variable region determines the antiger Fig.1.12 Clonal selection.Each s ir tor functio nof th gen how the antibody will interact with various immune cells to dispose of anti- gen once it is bound. fully mature, a two-fold axis of s otr 0S1 ns each le and constant regions;the variable so that both chains to the antigen-binding specificity o se to a clor the antibody molecule.The functional properties of antibodies conferred by their constant regions are considered in Chapters 5 and 10 ted by the arly.There a e,ho vever,important diff nces betwee the two th receptor.as shown in Fig 4.is com sed of twp chains aua size,called the T-cell receptorand Bchains,each of which spansthe T-cell dBcari n and a constant region and binding antigen.The structures of both antibodies and T-cell receptors are
� Chapter 1: Basic Concepts in Immunology A single progenitor cell gives rise to a large number of lymphocytes, each with a different specHiclty �+� 0 Q 99999 "' '7 Removal of potentially seH-reactlve Immature lymphocytes by clonal deletion Q 99999 Ill Ill • • self antigens self antigens Pool of mature naive lymphocytes 999 • foreign antigen ProiHeration and differentiation of activated specific lymphocytes to form a clone of effector cells ����� (�) () () () () Effector cells eliminate antigen Fig. 1.12 Clonal selection. Each lymphoid progenitor gives rise to a large number of lymphocytes, each bearing a distinct antigen receptor. Lymphocytes with receptors that bind ubiquitous self antigens are eliminated before they become fully mature, ensuring tolerance to such self antigens. When a foreign antigen interacts with the receptor on a mature naive lymphocyte, that cell is activated and starts to divide. It gives rise to a clone of identical progeny, all of whose receptors bind the same antigen. Antigen specificity is thus maintained as the progeny proliferate and differentiate into effector cells. Once antigen has been eliminated by these effector cells, the immune response ceases, although some lymphocytes are retained to mediate immunological memory. on the tissues of the body and attacking them? Ray Owen had shown in the late 1940s that genetically different twin calves with a common placenta, and thus a shared placental blood circulation, were immunologically unresponsive, or tolerant, to one another's tissues: they did not make an immune response against each other. Peter Medawar then showed in 1953 that exposure to foreign tissues during embryonic development caused mice to become immunologically tolerant to these tissues. Burnet proposed that developing lymphocytes that are potentially self -reactive are removed before they can mature, a process known as clonal deletion. He has since been proved right in this too, although the mechanisms ofimmunological tolerance are still being worked out, as we shall see when we discuss the development of lymphocytes in Chapter 8, and some of the situations in which tolerance breaks down in Chapters 14 and 15. Clonal selection of lymphocytes is the single most important principle in adaptive immunity. Its four basic postulates are listed in Fig. 1.13. The last of the problems posed by the clonal selection theory-how the diversity of lymphocyte antigen receptors is generated-was solved in the 1970s, when advances in molecular biology made it possible to clone the genes encoding antibody molecules. 1-11 The structure of the antibody molecule illustrates the central puzzle of adaptive immunity. As discussed above, antibodies are the secreted form of the B cell's antigen receptor. Because they are produced in very large quantities in response to antigen, antibodies can be studied by traditional biochemical techniques; indeed, their structure was understood long before recombinant DNA technology made it possible to study the membrane-bound antigen receptors of B cells. The startling feature that emerged from the biochemical studies was that antibody molecules are composed of two distinct regions. One is a constant region that takes one of only four or five biochemically distinguishable forms; the other is a variable region that can be composed of a seemingly infinite variety of different amino acid sequences, forming subtly different structures that allow antibodies to bind specifically to an equally vast variety of antigens. This division is illustrated in Fig. 1.14, where the antibody is depicted as a Y-shaped molecule. The variable region determines the antigenbinding specificity of the antibody. There are two identical variable regions in an antibody molecule, and it thus has two identical antigen-binding sites. The constant region determines the effector function of the antibody: that is, how the antibody will interact with various immune cells to dispose of antigen once it is bound. Each antibody molecule has a two-fold axis of symmetry and is composed of two identical heavy chains and two identical light chains (see Fig. 1.14). Heavy and light chains each have variable and constant regions; the variable regions of a heavy chain and a light chain combine to form an antigen-binding site, so that both chains contribute to the antigen-binding specificity of the antibody molecule. The functional properties of antibodies conferred by their constant regions are considered in Chapters 5 and 10. The T-cell receptor for antigen shows many similarities to the B -cell antigen receptor, and the two molecules are clearly related to each other evolutionarily. There are, however, important differences between the two that, as we shall see, relate to their different roles within the immune system. The T-cell receptor, as shown in Fig. 1.14, is composed of two chains of roughly equal size, called the T-cell receptor a and � chains, each of which spans the T-cell membrane. Each chain has a variable region and a constant region, and the combination of the a- and �-chain variable regions creates a single site for binding antigen. The structures of both antibodies and T-cell receptors are
Principles of innate and adaptive immunity 15 Postulates of the clonal selection hypothesis 5gi3lerbasepmcpleeof r 限德。 described in detail in Chapter 4,and how the diversity of the antigen-receptor repertoire is generated is detailed in Chapter 5. There is,howe recept en molecules directly but instead recognizes y I c ed and ell receptor the functionof the to the 1-12 How are antigen receptors with an almost infinite range of specificitie when Su by a ite nu able regions are inherited as sets of gene segments,each encoding a part of thevaiableegionofoneafheinmenoeobetnpopepitchimerPibf ioined by DNA recombination to form a stretch of DNA encoding a complete 1.14 Sche natic structure which is d Bcells as an a e Schematic structure of the T-cell receptor mpo ch arm of the rmed by a lic ains the Th constant regon the bound ole and a const receptor is not produced in a secreted fomm
Postulates of the clonal selection hypothesis Each lymphocyte bears a single type of receptor with a unique specificity Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high affinity leads to lymphocyte activation The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity to those of the parental cell from which that lymphocyte was derived Lymphocytes bearing receptors specific for ubiquitous self molecules are deleted at an early stage in lymphoid cell development and are therefore absent from the repertoire of mature lymphocytes described in detail in Chapter 4, and how the diversity of the antigen -receptor repertoire is generated is detailed in Chapter 5. There is, however, a crucial difference in the way in which the B-cell and T-cell receptors bind antigens: the T-cell receptor does not bind antigen molecules directly but instead recognizes fragments of antigens bound on the surface of other cells. The exact nature of the antigen recognized by T cells, and how the antigens are fragmented and carried to cell surfaces, is the subject of Chapter 6. A further difference from the antibody molecule is that there is no secreted form of the T-cell receptor; the function of the receptor is solely to signal to the T cell that it has bound its antigen, and the subsequent immunological effects depend on the actions of the T cells themselves, as we describe in Chapter 9. 1-12 Each developing lymphocyte generates a unique antigen receptor by rearranging its receptor gene segments. How are antigen receptors with an almost infinite range of specificities encoded by a finite number of genes? This question was answered in 1976, when Susumu Tonegawa discovered that the genes for immunoglobulin variable regions are inherited as sets of gene segments, each encoding a part of the variable region of one of the immunoglobulin polypeptide chains. During B-cell development in the bone marrow, these gene segments are irreversibly joined by DNA recombination to form a stretch of DNA encoding a complete variable region. How the complete antigen receptors are assembled from incomplete gene segments is the topic of Chapter 5. Fig. 1.14 Schematic structure of antigen receptors. Upper panel: an antibody molecule, which is secreted by activated B cells as an antigen-binding effector molecule. A membrane-bound version of this molecule acts as the B-cell antigen receptor (not shown). An antibody is composed of two identical heavy chains (green) and two identical light chains (yellow). Each chain has a constant part (shaded blue) and a variable part (shaded red). Each arm of the antibody molecule is formed by a light chain and a heavy chain such that the variable parts of the two chains come together, creating a variable region that contains the antigen-binding site. The stem is formed from the constant parts of the heavy chains and takes a limited number of forms. This constant region is involved in the elimination of the bound antigen. Lower panel: aT-cell antigen receptor. This is also composed of two chains, an a chain (yellow) and a � chain (green), each of which has a variable and a constant part. As with the antibody molecule, the variable parts of the two chains create a variable region, which forms the antigen-binding site. The T-cell receptor is not produced in a secreted form. Principles of innate and adaptive immunity � Fig. 1.13 The four basic principles of clonal selection. Schematic structure of an antibody molecule variable region (antigenbinding site) constant region (effector function) Schematic structure of the T-cell receptor a i3 � variable region (antigen-binding site) constant region �
16 Chapter 1:Basic Concepts in Immunology Here,we need only mention two features of these mechanisms.First,it is the ber of different gene segments tha nents can generate a vast numbero ensure ocyte expresses in The potential diversity of lymphocyte receptors generated in this way is ors is furthe created by adding orsubtracting nucleotides in the process ofjoining the gene segments variable this combinatorial diversity.In this way,a small amount of genetic materia can encode a truly staggering diversity of receptors Only subset of these erthe are lymphocytes of at least 10 different specificities in an individual human at any one time.These provide the raw material on which clonal selection acts 一epitope 1-13 mmunoglobulins bind a wide variety of chemical structures, whereas the T-cell receptor is special zed to recognize foreign In principle,almost any chemical structure can be rec tive immune sy n as a ognicd6yheae n antigen.but the usual antigens encountered mizes a small part of the molecular strucrure mcue which is known asuchas ant or epitope( Peogedbydeeatanigeneceptoesmay d on it 115 nse 是g然i6@ to and neutralize these antig ns and patl In contrast tors peptides bound to proteins on the surface ontin cells 6).A main sour the efector is derived from within the mnfected cell.T-ce th rge ar (MHC)TheeyT-ell th pepouneWe ho they gnize epitopes I receptors ai they are
� Chapter 1: Basic Concepts in Immunology Fig. 1.15 Antigens are the molecules recognized by the immune response, while epitopes are sites within antigens to which antigen receptors bind. Antigens can be complex macromolecules such as proteins, as shown in yellow. Most antigens are larger than the sites on the antibody or antigen receptor to which they bind, and the actual portion of the antigen that is bound is known as the antigenic determinant, or epitope, for that receptor. Large antigens such as proteins can contain more than one epitope (indicated in red and blue), and thus may bind different antibodies. Antibodies generally recognize epitopes on the surface of the antigen. Here, we need only mention two features of these mechanisms. First, it is the combinatorial assembly of a large number of different gene segments that makes possible the enormous size of the antigen receptor repertoire. This means that a finite number of gene segments can generate a vast number of different proteins. Second, the assembly process is regulated in a manner that ensures that each lymphocyte expresses only one receptor specificity. Third, because gene segment rearrangement involves an irreversible change in a cell's DNA, all the progeny of that cell will inherit genes encoding the same receptor specificity. This general scheme was later also confirmed for the genes encoding the antigen receptor on T cells. The potential diversity of lymphocyte receptors generated in this way is enormous. Just a few hundred different gene segments can combine in different ways to generate thousands of different receptor chains. The diversity of lymphocyte receptors is further amplified by junctional diversity, created by adding or subtracting nucleotides in the process of joining the gene segments, and by the fact that each receptor is made by pairing two different variable chains, each encoded by distinct sets of gene segments. A thousand different chains of each type could thus generate 106 distinct antigen receptors through this combinatorial diversity. In this way, a small amount of genetic material can encode a truly staggering diversity of receptors. Only a subset of these randomly generated receptor specificities survive the selective processes that shape the peripheral lymphocyte repertoire; nevertheless, there are lymphocytes of at least 108 different specificities in an individual human at any one time. These provide the raw material on which clonal selection acts. 1-13 Immunoglobulins bind a wide variety of chemical structures, whereas the T-cell receptor is specialized to recognize foreign antigens as peptide fragments bound to proteins of the major histocompatibility complex. In principle, almost any chemical structure can be recognized by the adaptive immune system as an antigen, but the usual antigens encountered in an infection are the proteins, glycoproteins, and polysaccharides of pathogens. An individual antigen receptor or antibody recognizes a small part of the molecular structure of an antigenic molecule, which is known as an antigenic determinant or epitope (Fig. 1.15). Macromolecular antigens such as proteins and glycoproteins usually have many different epitopes that can be recognized by different antigen receptors. The antigen receptors of B cells and T cells recognize antigen in fundamentally different ways. B cells directly recognize the native antigen that either has been secreted by a pathogen or is expressed on its surface (see Fig. 1.15). B cells eventually differentiate into effector plasma cells that secrete antibodies that will bind to and neutralize these antigens and pathogens. In contrast, T-cell receptors do not directly recognize native antigens. Rather, they recognize antigens that have been processed, partly degraded, and displayed as peptides bound to proteins on the surface of antigen-presenting cells (Fig. 1.16). A main source of the antigens recognized byT cells is cells infected with a pathogen, commonly a virus. In this case, the antigen that is recognized by the effector T cells is derived from within the infected cell. Importantly, T-cell receptors will only recognize antigen -derived pep tides when these are bound to particular cell-surface glycoproteins called MHC molecules, which are encoded in a cluster of genes called the major histocompatibility complex (MHC). The antigen recognized by T-cell receptors is thus a complex of a foreign peptide antigen and an MHC molecule (see Fig. 1.16). We shall see how these compound antigens are recognized byT-cell receptors and how they are generated in Chapters 4 and 6, respectively
Principles of innate and adaptive immunity 17 The T-cell receptor and a ecu most al s can r 笼 TCR the r eoeaga nel).It is in asa 1-14 The development and survival of lymphocytes is determined by signals received through their antigen receptors. The continuous generation of lymphocytes throughout life creates a prob- lem of keeping total numbers of peripheral lymphocytes relatively constan harCanTectaganstanndiiduarsomwmsefantigenswmlbeproducedBoh these problems seemtobe solved by making the survival of a lymphocyt epe deletion,as predicted by Bumets clonal selection theory,before they matur toa stage at which they could do damage.The compl signal Lymphocvtes that receive either too much or too signal during develop nbyfsuceclldpopogrmmed cell deat r or the de of l produces millions of new neutrophils.monocytes.red blood cells.and and be balanced by pha cel and spleen. vely short time ofits self-reactive recep and receptors are te ptor rep ertoir 1-15 Lymphocyes encounter and respond to antigen in the periphera organ Antigen and lymphocytes eventually encounter each other in the peripheral es,spl n and the muco lymphoid through these tissues.to which pathogen antigens are carried from sites
The epltopes recognized by T-cell receptors are often buried The antigen must first be broken down Into peptide fragments The epltope peptide binds to a self molecule, an MHC molecule The T-cell receptor binds to a complex of MHC molecule and epltope peptide 1-14 The development and survival of lymphocytes is determined by signals received through their antigen receptors. The continuous generation of lymphocytes throughout life creates a problem of keeping total numbers of peripheral lymphocytes relatively constant. In addition, with so many different antigen receptors being generated during lymphocyte development, it is inevitable that potentially dangerous receptors that can react against an individual's own self antigens will be produced. Both these problems seem to be solved by making the survival of a lymphocyte dependent on signals received through its antigen receptor. Lymphocytes that react strongly to self antigens during development are removed by clonal deletion, as predicted by Burnet's clonal selection theory, before they mature to a stage at which they could do damage. The complete absence of signals from the antigen receptor during development can also lead to cell death. Lymphocytes that receive either too much or too little signal during development are eliminated by a form of cell suicide called apoptosis or programmed cell death. Apoptosis, derived from a Greek word meaning the falling of leaves from the trees, is a general means of regulating the number of cells in the body. It is responsible, for example, for the death and shedding of old skin and intestinal epithelial cells, and the turnover of liver cells. Every day the bone marrow produces millions of new neutrophils, monocytes, red blood cells, and lymphocytes, and this production must be balanced by an equal loss. Most white blood cells are relatively short lived and die by apoptosis. The dying cells are phagocytosed and degraded by specialized macrophages in the liver and spleen. Lastly, if a lymphocyte's receptor is not used within a relatively short time of its entering the repertoire in the periphery, the cell bearing it dies, making way for new lymphocytes with different receptors. In this way, self-reactive receptors are eliminated, and receptors are tested to ensure that they are potentially functional. The mechanisms that shape and maintain the lymphocyte receptor repertoire are examined in Chapter 8. 1-15 Lymphocytes encounter and respond to antigen in the peripheral lymphoid organs. Antigen and lymphocytes eventually encounter each other in the peripheral lymphoid organs-the lymph nodes, spleen, and the mucosal lymphoid tissues (see Fig. 1.8). Mature naive lymphocytes are continually recirculating through these tissues, to which pathogen antigens are carried from sites Principles of innate and adaptive immunity � Fig. 1.16 T-cell receptors bind a complex of an antigen fragment and a self molecule. Unlike most antibodies, T-cell receptors can recognize epitopes that are buried within antigens (first panel). These antigens must first be degraded by proteinases (second panel), and the peptide epitope delivered to a self molecule, called an MHC molecule (third panel). It is in this form, as a complex of peptide and MHC molecule, that antigens are recognized by T-cell receptors (fourth panel)
18 Chapter 1:Basic Concepts in Immunology of infection,primarily by dendritic cells.The peripheral lymphoid organs arein-earing dendr composed of agg siomaceoee geomah1esdenciophage and dendritic cells. henanineainoniccms al fr gen and ant ent lymphatic vessels into the draining lymph nodes(Fig.1.17),peripheral e acti which then care means that an adaptive immune re se to an antigen that has not beer encountered befor does not become effec ive until about a week after infec tion（see Fig I tha recognize antigen or die. d h tem that co ar Iuic atio tissues under the pressure exerted by its continual production,and is carried by lymphatic vesse Afferent lymphatic vess and c arry pathogens the lymph node,while the dendritic cells actively migrate into the lymph node also attra ne outer cortex of the lyn s md to nodes enter the paracortical areas hrst and,because they are attracte by the edthere Free antigen diffusing through the lymph node can Fig.1.17 Cire ulating lymphocytes be an and thus become activated. a8dbeahekeem ivation of B cas de,wh e t T cells,a type of(see Section -)The location of B cells and vithin the lymph node is dynam and e of the follicle andT-cellzone wheretcells can their hemner func tion to b cells.Some of the b-cell follicles include germinal centers.where
� Chapter 1: Basic Concepts in Immunology Lymphocytes and lymph return to blood via the thoracic duct Naive lymphocytes enter lymph nodes from blood lymph node infected peripheral tissue Antigens from sites of infection reach lymph nodes via lymphatics Fig. 1.17 Circulating lymphocytes encounter antigen in peripheral lymphoid organs. Naive lymphocytes recirculate constantly through peripheral lymphoid tissue, here illustrated as a popliteal lymph node-a lymph node situated behind the knee. In the case of an infection in the foot, this will be the draining lymph node, where lymphocytes may encounter their specific antigens and become activated. Both activated and nonactivated lymphocytes are returned to the bloodstream via the lymphatic system. of infection, primarily by dendritic cells. The peripheral lymphoid organs are specialized to trap antigen-bearing dendritic cells and to facilitate the initiation of adaptive immune responses. Peripheral lymphoid tissues are composed of aggregations of lymphocytes in a framework of nonleukocyte stromal cells, which provide the basic structural organization of the tissue and provide survival signals to help sustain the life of the lymphocytes. Besides lymphocytes, peripheral lymphoid organs also contain resident macro phages and dendritic cells. When an infection occurs in a tissue such as the skin, free antigen and antigen-bearing dendritic cells travel from the site of infection through the afferent lymphatic vessels into the draining lymph nodes (Fig. 1. 17), peripheral lymphoid tissues where they activate antigen-specific lymphocytes. The activated lymphocytes then undergo a period of proliferation and differentiation, after which most leave the lymph nodes as effector cells via the efferent lymphatic vessel. This eventually returns them to the bloodstream (see Fig. 1.8), which then carries them to the tissues where they will act. This whole process takes about 4-6 days from the time that the antigen is recognized, which means that an adaptive immune response to an antigen that has not been encountered before does not become effective until about a week after infection (see Fig. 1.34). Naive lymphocytes that do not recognize their antigen also leave through the efferent lymphatic vessel and are returned to the blood, from which they continue to recirculate through lymphoid tissues until they recognize antigen or die. The lymph nodes are highly organized lymphoid organs located at the points of convergence of vessels of the lymphatic system, which is the extensive system that collects extracellular fluid from the tissues and returns it to the blood (see Fig. 1.8). This extracellular fluid is produced continuously by filtration from the blood and is called lymph. Lymph flows away from the peripheral tissues under the pressure exerted by its continual production, and is carried by lymphatic vessels, or lymphatics. One-way valves in the lymphatic vessels prevent a reverse flow, and the movements of one part of the body in relation to another are important in driving the lymph along. Afferent lymphatic vessels drain fluid from the tissues and carry pathogens and antigen-bearing cells from infected tissues to the lymph nodes (Fig. 1. 18). Free antigens simply diffuse through the extracellular fluid to the lymph node, while the dendritic cells actively migrate into the lymph node, attracted by chemokines. The same chemokines also attract lymphocytes from the blood, and these enter lymph nodes by squeezing through the walls of specialized blood vessels called high endothelial venules (HEV). In the lymph nodes, B lymphocytes are localized in follicles, which make up the outer cortex of the lymph node, with T cells more diffusely distributed in the surrounding paracortical areas, also referred to as the deep cortex or T-cell zones (see Fig. 1. 18). Lymphocytes migrating from the blood into lymph nodes enter the paracortical areas first and, because they are attracted by the same chemokines, antigen-presenting dendritic cells and macrophages also become localized there. Free antigen diffusing through the lymph node can become trapped on these dendritic cells and macro phages. This juxtaposition of antigen, antigen-presenting cells, and naive T cells in the T-cell zone creates an ideal environment in which naive T cells can bind their specific antigen and thus become activated. As noted earlier, activation of B cells usually requires not only antigen, which binds to the B-cell receptor, but also the cooperation of activated helper T cells, a type of effector T cell (see Section 1-4). The location of B cells and T cells within the lymph node is dynamically regulated by their state of activation. When they become activated, T cells and B cells both move to the border of the follicle and T-cell zone, where T cells can first provide their helper function to B cells. Some of the B-cell follicles include germinal centers, where