Principles of innate and adaptive immunity (2024)

1-5. Most infectious agents induce inflammatory responses by activating innateimmunity

Microorganisms such as bacteria that penetrate the epithelial surfaces of thebody for the first time are met immediately by cells and molecules that canmount an innate immune response. Phagocytic macrophages conduct the defenseagainst bacteria by means of surface receptors that are able to recognize andbind common constituents of many bacterial surfaces. Bacterial molecules bindingto these receptors trigger the macrophage to engulf the bacterium and alsoinduce the secretion of biologically active molecules. Activated macrophagessecrete cytokines, which aredefined as proteins released by cells that affect the behavior of other cellsthat bear receptors for them. They also release proteins known as chemokines that attract cells withchemokine receptors such as neutrophils and monocytes from the bloodstream(Fig. 1.12). The cytokines andchemokines released by macrophages in response to bacterial constituentsinitiate the process known as inflammation. Local inflammation and the phagocytosis of invadingbacteria may also be triggered as a result of the activation of complement on the bacterial cellsurface. Complement is a system of plasma proteins that activates a cascade ofproteolytic reactions on microbial surfaces but not on host cells, coating thesesurfaces with fragments that are recognized and bound by phagocytic receptors onmacrophages. The cascade of reactions also releases small peptides thatcontribute to inflammation.

Inflammation is traditionally defined by the four Latin wordscalor, dolor, rubor, andtumor, meaning heat, pain, redness, and swelling, all ofwhich reflect the effects of cytokines and other inflammatory mediators on thelocal blood vessels. Dilation and increased permeability of the blood vesselsduring inflammation lead to increased local blood flow and the leakage of fluid,and account for the heat, redness, and swelling. Cytokines and complementfragments also have important effects on the adhesive properties of theendothelium, causing circulating leukocytes to stick to the endothelial cells ofthe blood vessel wall and migrate between them to the site of infection, towhich they are attracted by chemokines. The migration of cells into the tissueand their local actions account for the pain. The main cell types seen in aninflammatory response in its initial phases are neutrophils, which are recruitedinto the inflamed, infected tissue in large numbers. Like macrophages, they havesurface receptors for common bacterial constituents and complement, and they arethe principal cells that engulf and destroy the invading micro-organisms. Theinflux of neutrophils is followed a short time later by monocytes that rapidlydifferentiate into macrophages. Macrophages and neutrophils are thus also knownas inflammatory cells. Inflammatory responses later in an infectionalso involve lymphocytes, which have meanwhile been activated by antigen thathas drained from the site of infection via the afferent lymphatics.

The innate immune response makes a crucial contribution to the activation ofadaptive immunity. The inflammatory response increases the flow of lymphcontaining antigen and antigen-bearing cells into lymphoid tissue, whilecomplement fragments on microbial surfaces and induced changes in cells thathave taken up microorganisms provide signals that synergize in activatinglymphocytes whose receptors bind to specific microbial antigens. Macrophagesthat have phagocytosed bacteria and become activated can also activate Tlymphocytes. However, the cells that specialize in presenting antigen to Tlymphocytes and initiating adaptive immunity are the dendritic cells.

1-6. Activation of specialized antigen-presenting cells is a necessary first stepfor induction of adaptive immunity

The induction of an adaptive immune response begins when a pathogen is ingestedby an immature dendritic cell in the infected tissue. Thesespecialized phagocytic cells are resident in most tissues and are relativelylong-lived, turning over at a slow rate. They derive from the same bone marrowprecursor as macrophages, and migrate from the bone marrow to their peripheralstations, where their role is to survey the local environment for pathogens.Eventually, all tissue-resident dendritic cells migrate through the lymph to theregional lymph nodes where they interact with recirculating naive lymphocytes.If the dendritic cells fail to be activated, they induce tolerance to theantigens of self that they bear.

The immature dendritic cell carries receptors on its surface that recognizecommon features of many pathogens, such as bacterial cell wall proteoglycans. Aswith macrophages and neutrophils, binding of a bacterium to these receptorsstimulates the dendritic cell to engulf the pathogen and degrade itintracellularly. Immature dendritic cells are also continually taking upextracellular material, including any virus particles or bacteria that may bepresent, by the receptor-independent mechanism of macropinocytosis. The function of dendritic cells,however, is not primarily to destroy pathogens but to carry pathogen antigens toperipheral lymphoid organs and there present them to T lymphocytes. When adendritic cell takes up a pathogen in infected tissue, it becomes activated, andtravels to a nearby lymph node. On activation, the dendritic cell matures into ahighly effective antigen-presenting cell (APC) andundergoes changes that enable it to activate pathogen-specific lymphocytes thatit encounters in the lymph node (Fig.1.13). Activated dendritic cells secrete cytokines that influence bothinnate and adaptive immune responses, making these cells essential gatekeepersthat determine whether and how the immune system responds to the presence ofinfectious agents. We shall consider the maturation of dendritic cells and theircentral role in presenting antigens to T lymphocytes in Chapter 8.

1-7. Lymphocytes activated by antigen give rise to clones of antigen-specificcells that mediate adaptive immunity

The defense systems of innate immunity are effective in combating many pathogens.They are constrained, however, by relying on germline-encoded receptors torecognize microorganisms that can evolve more rapidly than the hosts theyinfect. This explains why they can only recognize microorganisms bearing surfacemolecules that are common to many pathogens and that have been conserved overthe course of evolution. Not surprisingly, many pathogenic bacteria have evolveda protective capsule that enables them to conceal these molecules and therebyavoid being recognized and phagocytosed. Viruses carry no invariant moleculessimilar to those of bacteria and are rarely recognized directly by macrophages.Viruses and encapsulated bacteria can, however, still be taken up by dendriticcells through the nonreceptor-dependent process of macropinocytosis. Moleculesthat reveal their infectious nature may then be unmasked, and the dendritic cellactivated to present their antigens to lymphocytes. The recognition mechanismused by the lymphocytes of the adaptive immune response has evolved to overcomethe constraints faced by the innate immune system, and enables recognition of analmost infinite diversity of antigens, so that each different pathogen can betargeted specifically.

Instead of bearing several different receptors, each recognizing a differentsurface feature shared by many pathogens, each naive lymphocyte entering thebloodstream bears antigen receptors of a single specificity. The specificity ofthese receptors is determined by a unique genetic mechanism that operates duringlymphocyte development in the bone marrow and thymus to generate millions ofdifferent variants of the genes encoding the receptor molecules. Thus, althoughan individual lymphocyte carries receptors of only one specificity, thespecificity of each lymphocyte is different. This ensures that the millions oflymphocytes in the body collectively carry millions of different antigenreceptor specificities—the lymphocytereceptor repertoire of the individual. During a person's lifetimethese lymphocytes undergo a process akin to natural selection; only thoselymphocytes that encounter an antigen to which their receptor binds will beactivated to proliferate and differentiate into effector cells.

This selective mechanism was first proposed in the 1950s by MacfarlaneBurnet to explain why antibodies, which can be induced in response tovirtually any antigen, are produced in each individual only to those antigens towhich he or she is exposed. He postulated the preexistence in the body of manydifferent potential antibody-producing cells, each having the ability to makeantibody of a different specificity and displaying on its surface amembrane-bound version of the antibody that served as a receptor for antigen. Onbinding antigen, the cell is activated to divide and produce many identicalprogeny, known as a clone; thesecells can now secrete clonotypicantibodies with a specificity identical to that of the surface receptor thatfirst triggered activation and clonal expansion (Fig. 1.14). Burnet called this the clonal selection theory.

1-8. Clonal selection of lymphocytes is the central principle of adaptiveimmunity

Remarkably, at the time that Burnet formulated his theory, nothingwas known of the antigen receptors of lymphocytes; indeed the function oflymphocytes themselves was still obscure. Lymphocytes did not take center stageuntil the early 1960s, when JamesGowans discovered that removal of the small lymphocytes from ratsresulted in the loss of all known adaptive immune responses. These immuneresponses were restored when the small lymphocytes were replaced. This led tothe realization that lymphocytes must be the units of clonal selection, andtheir biology became the focus of the new field of cellular immunology.

Clonal selection of lymphocytes with diverse receptors elegantly explainedadaptive immunity but it raised one significant intellectual problem. If theantigen receptors of lymphocytes are generated randomly during the lifetime ofan individual, how are lymphocytes prevented from recognizing antigens on thetissues of the body and attacking them? Ray Owen had shown in thelate 1940s that genetically different twin calves with a common placenta wereimmunologically tolerant of one another's tissues, that is, theydid not make an immune response against each other. Sir PeterMedawar then showed in 1953 that if exposed to foreign tissues duringembryonic development, mice become immunologically tolerant to these tissues.Burnet proposed that developing lymphocytes that arepotentially self-reactive are removed before they can mature, a process known asclonal deletion. He has sincebeen proved right in this too, although the mechanisms of tolerance are stillbeing worked out, as we shall see when we discuss the development of lymphocytesin Chapter 7.

Clonal selection of lymphocytes is the single most important principle inadaptive immunity. Its four basic postulates are listed in Fig. 1.15. The last of the problems posed by the clonalselection theory—how the diversity of lymphocyte antigen receptors isgenerated—was solved in the 1970s when advances in molecular biology made itpossible to clone the genes encoding antibody molecules.

1-9. The structure of the antibody molecule illustrates the central puzzle ofadaptive immunity

Antibodies, as discussed above, are the secreted form of the B-cell antigenreceptor or BCR. Because they are produced in very large quantities in responseto antigen, they can be studied by traditional biochemical techniques; indeed,their structure was understood long before recombinant DNA technology made itpossible to study the membrane-bound antigen receptors of lymphocytes. Thestartling feature that emerged from the biochemical studies was that an antibodymolecule is composed of two distinct regions. One is a constant region that can take one of only four or fivebiochemically distinguishable forms; the other is a variable region that can take an apparently infinitevariety of subtly different forms that allow it to bind specifically to anequally vast variety of different antigens.

This division is illustrated in the simple schematic diagram in Fig. 1.16, where the antibody is depicted asa Y-shaped molecule, with the constant region shown in blue and the variableregion in red. The two variable regions, which are identical in any one antibodymolecule, determine the antigen-binding specificity of the antibody; theconstant region determines how the antibody disposes of the pathogen once it isbound.

Each antibody molecule has a twofold axis of symmetry and is composed of twoidentical heavy chains and two identical light chains (Fig. 1.17). Heavy and light chains both have variable andconstant regions; the variable regions of a heavy and a light chain combine toform an antigen-binding site, so that both chains contribute to theantigen-binding specificity of the antibody molecule. The structure of antibodymolecules will be described in detail in Chapter 3, and the functional properties of antibodies conferred bytheir constant regions will be considered in Chapters 4 and 9. For the time being we are concerned only with the properties ofimmunoglobulin molecules as antigen receptors, and how the diversity of thevariable regions is generated.

1-10. Each developing lymphocyte generates a unique antigen receptor by rearrangingits receptor genes

How are antigen receptors with an almost infinite range of specificities encodedby a finite number of genes? This question was answered in 1976, when Susumu Tonegawa discovered that thegenes for immunoglobulin variable regions are inherited as sets of gene segments, each encoding a partof the variable region of one of the immunoglobulin polypeptide chains (Fig. 1.18). During B-cell development in thebone marrow, these gene segments are irreversibly joined by DNA recombination toform a stretch of DNA encoding a complete variable region. Because there aremany different gene segments in each set, and different gene segments are joinedtogether in different cells, each cell generates unique genes for the variableregions of the heavy and light chains of the immunoglobulin molecule. Once theserecombination events have succeeded in producing a functional receptor, furtherrearrangement is prohibited. Thus each lymphocyte expresses only one receptorspecificity.

This mechanism has three important consequences. First, it enables a limitednumber of gene segments to generate a vast number of different proteins. Second,because each cell assembles a different set of gene segments, each cellexpresses a unique receptor specificity. Third, because gene rearrangementinvolves an irreversible change in a cell's DNA, all the progeny of that cellwill inherit genes encoding the same receptor specificity. This general schemewas later also confirmed for the genes encoding the antigen receptor on Tlymphocytes. The main distinctions between B- and T-lymphocyte receptors arethat the immunoglobulin that serves as the B-cell antigen receptor has twoidentical antigen-recognition sites and can also be secreted, whereas the T-cellantigen receptor has a single antigen-recognition site and is always acell-surface molecule. We shall see later that these receptors also recognizeantigen in very different ways.

The potential diversity of lymphocyte receptors generated in this way isenormous. Just a few hundred different gene segments can combine in differentways to generate thousands of different receptor chains. The diversity oflymphocyte receptors is further amplified by junctional diversity, created byadding or subtracting nucleotides in the process of joining the gene segments,and by the fact that each receptor is made by pairing two different variablechains, each encoded in distinct sets of gene segments. A thousand differentchains of each type could thus generate 10⁶ distinct antigenreceptors through this combinatorialdiversity. Thus a small amount of genetic material can encode a trulystaggering diversity of receptors. Only a subset of these randomly generatedreceptor specificities survive the selective processes that shape the peripherallymphocyte repertoire; nevertheless, there are lymphocytes of at least10⁸ different specificities in an individual at any one time.These provide the raw material on which clonal selection acts.

1-11. Lymphocyte development and survival are determined by signals receivedthrough their antigen receptors

Equally amazing as the generation of millions of specificities of lymphocyteantigen receptors is the shaping of this repertoire during lymphocytedevelopment and the homeostatic maintenance of such an extensive repertoire inthe periphery. How are the most useful receptor specificities selected, and howare the numbers of peripheral lymphocytes, and the percentages of B cells and Tcells kept relatively constant? The answer seems to be that lymphocytematuration and survival are regulated by signals received through their antigenreceptors. Strong signals received through the antigen receptor by an immaturelymphocyte cause it to die or undergo further receptor rearrangement, and inthis way self-reactive receptor specificities are deleted from the repertoire.However, a complete absence of signals from the antigen receptor can also leadto cell death. It seems that in order to survive, lymphocytes must periodicallyreceive certain signals from their environment via their antigen receptors. Inthis way, the body can ensure that each receptor is functional and regulate thenumber and type of lymphocytes in the population at any given time. Thesesurvival signals appear to be delivered by other cells in the lymphoid organsand must derive, at least in part, from the body's own molecules, the self antigens, as altering the selfenvironment alters the life-span of lymphocytes in that environment. DevelopingB cells in the bone marrow interact with stromal cells, while their finalmaturation and continued recirculation appears to depend on survival signalsreceived from the B-cell follicles of peripheral lymphoid tissue. T lymphocytesreceive survival signals from self molecules on specialized epithelial cells inthe thymus during development, and from the same molecules expressed bydendritic cells in the lymphoid tissues in the periphery. The self ligands thatinteract with the T-cell receptor to deliver these signals are partiallydefined, being composed of known cell-surface molecules complexed with undefinedpeptides from other self proteins in the cell. These same cell-surface moleculesfunction to present foreign intracellular antigens to T cells, as we shallexplain in Section 1-16, and in Chapter 5. They select only a subsetof T-cell receptors for survival, but these are the receptors most likely to beuseful in responding to foreign antigens, as we shall see in Chapter 7.

Lymphocytes that fail to receive survival signals, and those that are clonallydeleted because they are self-reactive, undergo a form of cell suicide calledapoptosis or programmed cell death. Apoptosis,derived from a Greek word meaning the falling of leaves from the trees, occursin all tissues, at a relatively constant rate in each tissue, and is a means ofregulating the number of cells in the body. It is responsible, for example, forthe death and shedding of skin cells, the turnover of liver cells, and the deathof the oldest intestinal epithelial cells that are constantly replaced by newcells. Thus, it should come as no surprise that immune system cells areregulated through the same mechanism. Each day the bone marrow produces manymillions of new neutrophils, monocytes, red blood cells, and lymphocytes, andthis production must be balanced by an equal loss of these cells. Regulated lossof all these blood cells occurs by apoptosis, and the dying cells are finallyphagocytosed by specialized macrophages in the liver and spleen. Lymphocytes area special case, because the loss of an individual naive lymphocyte means theloss of a receptor specificity from the repertoire, while each newly maturedcell that survives will contribute a different specificity. The survival signalsreceived through the antigen receptors appear to regulate this process byinhibiting the apoptosis of individual lymphocytes, thus regulating themaintenance and composition of the lymphocyte repertoire. We shall return to thequestion of which ligands deliver these signals, and how they contribute toshaping and maintaining the receptor repertoire, in Chapter 7.

1-12. Lymphocytes proliferate in response to antigen in peripheral lymphoid organs,generating effector cells and immunological memory

The large diversity of lymphocyte receptors means that there will usually be atleast a few that can bind to any given foreign antigen. However, because eachlymphocyte has a different receptor, the numbers of lymphocytes that can bindand respond to any given antigen is very small. To generate sufficientantigen-specific effector lymphocytes to fight an infection, a lymphocyte withan appropriate receptor specificity must be activated to proliferate before itsprogeny finally differentiate into effector cells. This clonal expansion is a feature commonto all adaptive immune responses.

As we have seen, lymphocyte activation and proliferation is initiated in thedraining lymphoid tissues, where naive lymphocytes and activatedantigen-presenting cells can come together. Antigens are thus presented to thenaive recirculating lymphocytes as they migrate through the lymphoid tissuebefore returning to the bloodstream via the efferent lymph. On recognizing itsspecific antigen, a small lymphocyte stops migrating and enlarges. The chromatinin its nucleus becomes less dense, nucleoli appear, the volume of both thenucleus and the cytoplasm increases, and new RNAs and proteins are synthesized.Within a few hours, the cell looks completely different and is known as a lymphoblast (Fig. 1.19).

The lymphoblasts now begin to divide, normally duplicating themselves two to fourtimes every 24 hours for 3 to 5 days, so that one naive lymphocyte gives rise toa clone of around 1000 daughter cells of identical specificity. These thendifferentiate into effector cells (see Fig.1.19). In the case of B cells, the differentiated effector cells, theplasma cells, secrete antibody; in the case of T cells, the effector cells areable to destroy infected cells or activate other cells of the immune system.These changes also affect the recirculation of antigen-specific lymphocytes.Changes in the cell-adhesion molecules they express on their surface alloweffector lymphocytes to migrate into sites of infection or stay in the lymphoidorgans to activate B cells.

After a naive lymphocyte has been activated, it takes 4 to 5 days before clonalexpansion is complete and the lymphocytes have differentiated into effectorcells. That is why adaptive immune responses occur only after a delay of severaldays. Effector cells have only a limited life-span and, once antigen is removed,most of the antigen-specific cells generated by the clonal expansion of smalllymphocytes undergo apoptosis. However, some persist after the antigen has beeneliminated. These cells are known as memory cells and form the basis of immunological memory, which ensures a more rapid andeffective response on a second encounter with a pathogen and thereby provideslasting protective immunity.

The characteristics of immunological memory are readily observed by comparing theantibody response of an individual to a first or primaryimmunization with the response elicited in the same individual by asecondary or boosterimmunization with the same antigen. As shown in Fig. 1.20, the secondary antibody response occurs after a shorter lag phase,achieves a markedly higher level, and produces antibodies of higher affinity, or strength of binding, forthe antigen. We shall describe the mechanisms of these remarkable changes inChapters 9 and 10. The cellular basis ofimmunological memory is the clonal expansion and clonal differentiation of cellsspecific for the eliciting antigen, and it is therefore entirely antigenspecific.

It is immunological memory that enables successful vaccination and preventsreinfection with pathogens that have been repelled successfully by an adaptiveimmune response. Immunological memory is the most important biologicalconsequence of the development of adaptive immunity, although its cellular andmolecular basis is still not fully understood, as we shall see in Chapter 10.

1-13. Interaction with other cells as well as with antigen is necessary forlymphocyte activation

Peripheral lymphoid tissues are specialized not only to trap phagocytic cellsthat have ingested antigen (see Sections1-3 and 1-6) but also topromote their interactions with lymphocytes that are needed to initiate anadaptive immune response. The spleen and lymph nodes in particular are highlyorganized for the latter function.

All lymphocyte responses to antigen require not only the signal that results fromantigen binding to their receptors, but also a second signal, which is deliveredby another cell. Naive T cells are generally activated by activated dendriticcells (Fig. 1.21, left panel) but for Bcells (Fig. 1.21, right panel), the secondsignal is delivered by an armed effector T cell. Because of their ability todeliver activating signals, these three cell types are known asprofessional antigen-presenting cells, or often just antigen-presenting cells. They areillustrated in Fig. 1.22. Dendritic cellsare the most important antigenpresenting cell of the three, with a central rolein the initiation of adaptive immune responses (see Section 1-6). Macrophages can also mediate innate immuneresponses directly and make a crucial contribution to the effector phase of theadaptive immune response. B cells contribute to adaptive immunity by presentingpeptides from antigens they have ingested and by secreting antibody.

Thus, the final postulate of adaptive immunity is that it occurs on a cell thatalso presents the antigen. This appears to be an absolute rule invivo, although exceptions have been observed in invitro systems. Nevertheless, what we are attempting to define iswhat does happen, not what can happen.

Summary

The early innate systems of defense, which depend on invariant receptorsrecognizing common features of pathogens, are crucially important, but they areevaded or overcome by many pathogens and do not lead to immunological memory.The abilities to recognize all pathogens specifically and to provide enhancedprotection against reinfection are the unique features of adaptive immunity,which is based on clonal selection of lymphocytes bearing antigen-specificreceptors. The clonal selection of lymphocytes provides a theoretical frameworkfor understanding all the key features of adaptive immunity. Each lymphocytecarries cell-surface receptors of a single specificity, generated by the randomrecombination of variable receptor gene segments and the pairing of differentvariable chains. This produces lymphocytes, each bearing a distinct receptor, sothat the total repertoire of receptors can recognize virtually any antigen. Ifthe receptor on a lymphocyte is specific for a ubiquitous self antigen, the cellis eliminated by encountering the antigen early in its development, whilesurvival signals received through the antigen receptor select and maintain afunctional lymphocyte repertoire. Adaptive immunity is initiated when an innateimmune response fails to eliminate a new infection, and antigen and activatedantigen-presenting cells are delivered to the draining lymphoid tissues. When arecirculating lymphocyte encounters its specific foreign antigen in peripherallymphoid tissues, it is induced to proliferate and its progeny thendifferentiate into effector cells that can eliminate the infectious agent. Asubset of these proliferating lymphocytes differentiate into memory cells, readyto respond rapidly to the same pathogen if it is encountered again. The detailsof these processes of recognition, development, and differentiation form themain material of the middle three parts of this book.