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Home , Adaptive immune system, Dendritic cell, Humoral immunity, Immune system, Immunity (medical), Immunodeficiency

1 Introduction to the Nomenclature, General Properties, and Components

CHAPTER OUTLINE Innate and Adaptive , 3 -Presenting Cells, 14 Types of Adaptive Immunity, 4 Tissues of the Immune System, 15 Properties of Adaptive Immune Responses, 6 Peripheral (Secondary) Lymphoid Organs and Specificity and Diversity, 6 Tissues, 15 Memory, 7 Recirculation and Migration into Other Features of Adaptive Immunity, 8 Tissues, 20 Cells of the , 9 Summary, 21 , 9

The term “immunity” in a biologic context has his- a more inclusive definition of the is a torically referred to resistance to ; however, reaction to microbes, as well as to other that reactions to some noninfectious substances including are recognized as foreign, regardless of the physiologic or harmless environmental molecules, tumors, and even pathologic consequence of such a reaction. is unaltered host components are also considered forms of the study of immune responses in this broader sense and of immunity (, tumor immunity, and , the cellular and molecular events that occur after an - respectively). The collection of cells, tissues, and mole- ism encounters microbes and other foreign molecules. cules that mediate these reactions is called the immune The importance of the immune system for health system, and the coordinated response of these cells and is dramatically illustrated by the frequent observation molecules to pathogens and other substances comprises that individuals with defective immune responses are an immune response. susceptible to serious, often -threatening . The most important physiologic function of the Conversely, stimulating immune responses against immune system is to prevent or eradicate infections microbes through is the most effective (Fig. 1.1), and this is the principal context in which immune method for protecting individuals against infections; responses are discussed throughout this book. In addition, this approach has led to the worldwide eradication of it prevents the growth of some tumors, and some , the only that has been eliminated can be treated by stimulating immune responses against from civilization by intervention (Fig. 1.2). The tumor cells. The immune system also plays a major role in appearance of acquired syndrome the repair of damaged tissues. Because the immune system (AIDS) in the 1980s tragically emphasized the impor- can respond to microbial and nonmicrobial substances tance of the immune system for defending individuals and also can cause disease under some circumstances, against .

1 2 CHAPTER 1 Introduction to the Immune System

Role of the immune system Implications Defense against infections Deficient immunity results in increased susceptibility to infections; exemplified by AIDS Vaccination boosts immune defenses and protects against infections Defense against tumors Potential for of Control of Repair of damaged tissues and scarring The immune system can Immune responses are the cause injure cells and induce of allergic, autoimmune, and other pathologic inflammatory The immune system Immune responses are barriers to recognizes and responds transplantation and to tissue grafts and newly introduced Fig. 1.1 Importance of the immune system in health and disease. This table summarizes some of the phys- iologic functions of the immune system and its role in disease. AIDS, Acquired immunodeficiency syndrome. In contrast to these beneficial roles, abnormal immune • How are the cells and tissues of the immune system responses cause many inflammatory diseases with seri- organized to find and respond to microbes in ways ous morbidity and mortality. The immune response is that lead to their elimination? the major barrier to the success of , The basic principles introduced here set the stage for which is often used to treat organ failure. The products more detailed discussions of immune responses in later of immune cells can also be of great practical use. For chapters. A Glossary of the important terms used in this example, , which are proteins made by certain book is provided near the end of the book. cells of the immune system, are used in clinical labora- tory testing and in research as highly specific reagents INNATE AND ADAPTIVE IMMUNITY for detecting a wide variety of molecules in the circu- lation and in cells and tissues. Antibodies designed to Host defenses are grouped under innate immunity, block or eliminate potentially harmful molecules and which provides immediate protection against micro- cells are used widely for the treatment of immunologic bial invasion, and adaptive immunity, which develops diseases, cancers, and other types of disorders. For all more slowly and provides more specialized defense these reasons, the field of immunology has captured the against infections (Fig. 1.3). Innate immunity, also attention of clinicians, scientists, and the lay public. called natural immunity or native immunity, is always This chapter introduces the nomenclature of immu- present in healthy individuals (hence the term innate), nology, important general properties of all immune prepared to block the entry of microbes and to rapidly responses, and the cells and tissues that are the principal eliminate microbes that do succeed in entering host tis- components of the immune system. In particular, the sues. Adaptive immunity, also called specific immunity following questions are addressed: or acquired immunity, requires proliferation and differ- • What types of immune responses protect individuals entiation of lymphocytes in response to microbes before from infections? it can provide effective defense (i.e., it adapts to the pres- • What are the important characteristics of immunity, ence of microbial invaders). Innate immunity is phylo- and what mechanisms are responsible for these char- genetically older, and the more specialized and powerful acteristics? adaptive immune response evolved later. CHAPTER 1 Introduction to the Immune System 3

Disease Maximum number Number of of cases (year) cases in 2014

Diptheria 206,939 (1921) 0 894,134 (1941) 72 152,209 (1968) 40 Pertussis 265,269 (1934) 311 21,269 (1952) 0 (paralytic) 57,686 (1969) 0 1,560 (1923) 0 Hemophilus ~20,000 (1984) 134 influenzae type B infection B 26,611 (1985) 58 Fig. 1.2 Effectiveness of vaccination for some common infectious diseases in the United States. Many infectious diseases for which effective have been developed have been virtually eradicated in the United States and other developed countries. (Modified from Orenstein WA, Hinman AR, Bart KJ, Hadler SC. . In: Mandell GL, Bennett JE, Dolin R, editors: Principles and practices of infectious diseases, 4th ed. New York: Churchill Livingstone, 1995; and MMWR 66, No. 1, 2017.)

In innate immunity, the first line of defense is pro- recognize a much wider variety of molecules produced vided by epithelial barriers of the and mucosal by microbes, as well as noninfectious molecules. Any tissues and by cells and natural present in that is specifically recognized by lymphocytes epithelia, all of which function to block the entry of or antibodies is called an antigen. Adaptive immune microbes. If microbes do breach epithelia and enter the responses often use the cells and molecules of the innate tissues or circulation, several other components of the immune system to eliminate microbes. For example, defend against them, includ- antibodies (a component of adaptive immunity) bind to ing and innate lymphoid cells, and several microbes, and these coated microbes avidly bind to and plasma proteins, such as the . In activate phagocytes (a component of innate immunity), addition to providing early defense against infections, which ingest and destroy the microbes. Examples of the innate immune responses are required to initiate adap- cooperation between innate and adaptive immunity are tive immune responses against the infectious agents. discussed in later chapters. The components and mechanisms of innate immunity By convention, the term immune response generally are discussed in detail in Chapter 2. refers to adaptive immunity, and that is the focus of The adaptive immune system consists of lympho- most of this chapter. cytes with highly diverse and variable receptors for The cells of the immune system are located in dif- foreign substances, and the products of these cells, ferent tissues and serve different roles in host defense. such as antibodies. Adaptive immune responses are Most of these cells are derived from marrow pre- essential for defense against infectious microbes that are cursors that circulate in the and are called leuko- pathogenic for (i.e., capable of causing disease) cytes (white blood cells). Others are present in tissues at and may have evolved to resist innate immunity. The cells all times. Some of these cells function mainly in innate and molecules of innate immunity recognize structures immunity, others in adaptive immunity, and some func- shared by classes of microbes, whereas the lymphocytes tion in both types of responses. These cells are grouped of adaptive immunity express receptors that specifically into two broad categories—lymphoid cells (most of 4 CHAPTER 1 Introduction to the Immune System

Microbe Innate immunity Adaptive immunity Antibodies Epithelial barriers

B lymphocytes Plasma cells Mast Dendritic cells cells Phagocytes

NK cells T lymphocytes Complement and ILCs Effector T cells Hours Days 0612 135 Time after infection Fig. 1.3 Principal mechanisms of innate and adaptive immunity. The mechanisms of innate immunity provide the initial defense against infections. Some mechanisms (e.g., epithelial barriers) prevent infections, and other mechanisms (e.g., phagocytes, natural killer [NK] cells and other innate lymphoid cells [ILCs], the complement system) eliminate microbes. Adaptive immune responses develop later and are mediated by lymphocytes and their products. Antibodies block infections and eliminate microbes, and T lymphocytes erad- icate intracellular microbes. The kinetics of the innate and adaptive immune responses are approximations and may vary in different infections.

which are the mediators of adaptive immune responses) sentinels and phagocytes are primarily cells of innate and nonlymphoid cells, also called myeloid cells, immunity, they are described in Chapter 2. which play diverse roles, including in innate immune • Lymphocytes, including B and T cells, circulate responses. through lymphoid organs and nonlymphoid tissues. • Tissue-resident dendritic cells, , and They recognize foreign and carry out adap- mast cells serve as sentinels to detect the presence of tive immune responses. They are described further microbes in tissues and initiate immune responses. later in this chapter. Dendritic cells (DCs), so called because of their many protruding membrane extensions, also have TYPES OF ADAPTIVE IMMUNITY the specialized function of capturing microbial anti- gens and displaying them to T lymphocytes to ini- The two types of adaptive immunity, called humoral tiate adaptive immune responses and are therefore immunity and -mediated immunity, are mediated called antigen-presenting cells (APCs, discussed by different cells and molecules and provide defense later). against extracellular microbes and intracellular • Phagocytes ingest and destroy microbes. They are microbes, respectively (Fig. 1.4). myeloid cells and include , which are •  is mediated by proteins called recruited from the blood, and macrophages, which antibodies, which are produced by cells called can develop from circulating and live in B lymphocytes. Secreted antibodies enter the circu- tissues much longer than neutrophils do. Macrophages lation, extracellular tissue fluids, and the lumens of are not only sentinels and destroyers of microbes, mucosal organs such as the gastrointestinal and respi- they also help to repair damaged tissues. Because the ratory tracts. The antibodies defend against microbes CHAPTER 1 Introduction to the Immune System 5

Humoral Cell-mediated immunity immunity

Microbe

Intracellular microbes Extracellular Phagocytosed (e.g., ) microbes microbes in replicating within infected cell

Responding lymphocytes Helper Cytotoxic B lymphocyte T lymphocyte T lymphocyte

Cytokines Secreted Effector mechanism

Block Activated Killed infected cell infections macrophage and Kill infected cells Functions eliminate Elimination of and eliminate extracellular phagocytosed reservoirs microbes microbes of infection Fig. 1.4 Types of adaptive immunity. In humoral immunity, B lymphocytes secrete antibodies that elimi- nate extracellular microbes. In cell-mediated immunity, some T lymphocytes secrete soluble proteins called that recruit and activate phagocytes to destroy ingested microbes, and other T lymphocytes kill infected cells.

present in these locations by preventing them from it is mediated by cells, which are called T lympho- invading tissue cells and by neutralizing made cytes. Cell-mediated immunity is especially import- by the microbes. Microbes that live and divide out- ant to defend against intracellular that side cells but are readily killed once ingested by can survive and replicate inside cells. Some T lym- phagocytes are called extracellular microbes, and phocytes activate phagocytes to destroy microbes antibodies can enhance the uptake of these microbes that have been ingested and live within intracellular into phagocytes. However, many microbes, often vesicles of these phagocytes. Other T lymphocytes called intracellular microbes, can live and divide kill any type of host cells (including non-phagocytic inside infected cells, including phagocytes. Although cells) that harbor infectious microbes in the cyto- antibodies can prevent such microbes from infecting plasm or nucleus. In both cases, the T cells recognize tissue cells, they are not effective after the microbes microbial antigens that are displayed on host cell sur- have entered the cells. faces, which indicates there is a microbe inside the • Defense against microbes that have already entered cell. Some T lymphocytes also help to defend against host cells is called cell-mediated immunity because extracellular microbes by recruiting large numbers of 6 CHAPTER 1 Introduction to the Immune System

phagocytes to sites of infection, and the phagocytes Feature Functional significance ingest and destroy the microbes. The specificities of B and T lymphocytes differ in Specificity Ensures that immune important respects. Most T cells recognize only peptide responses are precisely fragments of antigens presented on cell surfaces, targeted to microbial pathogens whereas B cells and antibodies are able to recognize many different types of molecules, including proteins, Diversity Enables immune system , nucleic , and lipids. These and other to respond to a large variety of antigens differences are discussed in more detail later. Immunity may be induced in an individual by Memory Leads to enhanced responses to repeated exposures to the infection or vaccination (active immunity) or con- same antigens ferred on an individual by transfer of antibodies or lymphocytes from an actively immunized individual Clonal Increases number of expansion antigen-specific lymphocytes (). from a small number of • In active immunity, an individual exposed to the naive lymphocytes antigens of a microbe mounts a response to eradicate Specialization Generates responses that are the infection and develops resistance to later infec- optimal for defense against tion by that microbe. Such an individual is said to different types of microbes be immune to that microbe, in contrast with a naive Contraction and Allows immune system individual who has not previously been exposed to homeostasis to respond to newly that microbe’s antigens. encountered antigens • In passive immunity, a naive individual receives anti- Nonreactivity Prevents injury to the bodies or cells (e.g., lymphocytes) from another indi- to self host during responses to vidual already immune to an infection or protective foreign antigens antibodies that have been synthesized using modern Fig. 1.5 Properties of adaptive immune responses. This bioengineering techniques. The recipient acquires table summarizes the important properties of adaptive immune the ability to combat the infection for as long as the responses and how each feature contributes to host defense transferred antibodies or cells last. Passive immunity against microbes. is therefore useful for rapidly conferring immunity even before the individual is able to mount an active response, but it does not induce long-lived resistance Specificity and Diversity to the infection. The only physiologic example of pas- sive immunity is seen in newborns, whose immune The adaptive immune system is capable of distin- systems are not mature enough to respond to many guishing millions of different antigens or portions pathogens but who are protected against infections by of antigens, a feature that is referred to as specificity. acquiring antibodies during fetal life from their moth- It implies that the total collection of lymphocyte spec- ers through the and in the neonatal period ificities, sometimes called the lymphocyte repertoire, from . Clinically, passive immunity is use- is extremely diverse. The total population of B and T ful for treating some immunodeficiency diseases with lymphocytes consists of many different clones (each antibodies pooled from multiple donors and for emer- made up of cells all derived from one lympho- gency treatment of some viral infections and snakebites cyte), and all the cells of one clone express identical using from immunized donors. Antibodies and antigen receptors, which are different from the recep- T cells designed to recognize tumors are now widely tors of all other clones. We now know the molecular used for passive immunotherapy of cancers. basis for the generation of this remarkable diversity of lymphocytes (see Chapter 4). Theclonal selection PROPERTIES OF ADAPTIVE IMMUNE hypothesis, formulated in the 1950s, correctly pre- RESPONSES dicted that clones of lymphocytes specific for different antigens develop before an encounter with these anti- Several properties of adaptive immune responses are gens, and each antigen elicits an immune response by crucial for the effectiveness of these responses in com- selecting and activating the lymphocytes of a specific bating infections (Fig. 1.5). clone (Fig. 1.6). CHAPTER 1 Introduction to the Immune System 7

Lymphocyte Mature precursor lymphocyte Lymphocyte clones with diverse receptors arise in generative lymphoid organs

Clones of mature lymphocytes specific for many antigens enter lymphoid tissues Antigen X Antigen Y

Antigen-specific clones are activated ("selected") by antigens

Antigen-specific immune responses occur Anti-X Anti-Y antibody antibody Fig. 1.6 . Mature lymphocytes with receptors for many antigens develop before encoun- tering these antigens. A clone refers to a population of lymphocytes with identical antigen receptors and therefore specificities; all of these cells are presumably derived from one precursor cell. Each antigen (e.g.,X and Y) selects a preexisting clone of specific lymphocytes and stimulates the proliferation and differentiation of that clone. The diagram shows only B lymphocytes giving rise to antibody-secreting cells, but the same principle applies to T lymphocytes. The antigens shown are surface molecules of microbes, but clonal selec- tion is true for all extracellular and intracellular antigens.

The diversity of the lymphocyte repertoire, which of lymphocytes specific for any antigen upon exposure enables the immune system to respond to a vast number to that antigen, the selection and preservation of the and variety of antigens, also means that before exposure most potent lymphocytes, and numerous positive feed- to any one antigen, very few cells, perhaps as few as 1 in back loops that amplify immune responses. These char- 100,000 or 1 in 1,000,000 lymphocytes, are specific for acteristics of the adaptive immune system are described that antigen. Thus, the total number of lymphocytes that in later chapters. can recognize and react against any one antigen ranges from approximately 1,000 to 10,000 cells. To mount an Memory effective defense against microbes, these few cells have The adaptive immune system mounts faster, larger to give rise to a large number of lymphocytes capable of and more effective responses to repeated exposure destroying the microbes. Each unique lymphocyte that to the same antigen. This feature of adaptive immune recognizes a single antigen and its progeny constitute responses implies that the immune system remembers an antigen-specific clone. The effectiveness of immune every encounter with antigen, and this property of adap- responses is attributable to several features of adaptive tive immunity is therefore called immunologic mem- immunity, including the marked expansion of the clone ory. The response to the first exposure to antigen, called 8 CHAPTER 1 Introduction to the Immune System the primary immune response, is initiated by lympho- Other Features of Adaptive Immunity cytes called naive lymphocytes that are seeing antigen Adaptive immune responses have other characteristics for the first time Fig.( 1.7). The termnaive refers to these that are important for their functions (see Fig. 1.5). cells being immunologically inexperienced, not having • When naive or memory lymphocytes are activated previously responded to antigens. Subsequent encoun- by antigens, they undergo proliferation, generating ters with the same antigen lead to responses called sec- many thousands of cells, all with the same antigen ondary immune responses that usually are more rapid, receptors and specificity. This process, called clonal larger, and better able to eliminate the antigen than expansion, rapidly increases the number of cells primary responses. Secondary responses are the result specific for the antigen encountered and ensures of the of memory lymphocytes, which are that adaptive immunity keeps pace with rapidly long-lived cells that were induced during the primary proliferating microbes. immune response. Immunologic memory optimizes • Immune responses are specialized, and different the ability of the immune system to combat persistent responses are designed to defend best against differ- and recurrent infections, because each exposure to a ent types of microbes. microbe generates more memory cells and activates pre- • All immune responses are self-limited and decline viously generated memory cells. Immunologic memory as the infection is eliminated, allowing the system to is one mechanism by which vaccines confer long-lasting return to a resting state (homeostasis), prepared to protection against infections. respond to another infection.

Antigen X + Antigen X Antigen Y Plasma cells Anti-X

Anti-Y B cell

Secondary Plasma anti-X cell response Plasma Memory cells B cells Naive Primary B cells Primary anti-X anti-Y response response Serum antibody titer 246810 Weeks Fig. 1.7 Primary and secondary immune responses. The properties of memory and specificity can be demonstrated by repeated with defined antigens in experiments. AntigensX and Y induce the production of different antibodies (a reflection of specificity). The secondary response to antigen X is more rapid and larger than the primary response (illustrating memory) and is different from the primary response to antigen Y (again reflecting specificity). Antibody levels decline with time after each immunization. The level of antibody produced is shown as arbitrary values and varies with the type of antigen exposure. Only B cells are shown, but the same features are seen with responses to antigens. The time after immunization may be 1 to 3 weeks for a primary response and 2 to 7 days for a secondary response, but the kinetics vary, depending on the antigen and the nature of immunization. CHAPTER 1 Introduction to the Immune System 9

• The immune system is able to react against an enor- (Fig. 1.8). Phagocytes and other cells of innate immunity mous number and variety of microbes and other for- are described in Chapter 2. eign antigens, but it normally does not react against the host’s own potentially antigenic substances— Lymphocytes so-called self antigens. This unresponsiveness to self Lymphocytes are the only cells that produce clonally is called immunological tolerance, referring to the distributed receptors specific for diverse antigens and ability of the immune system to coexist with (toler- are the key mediators of adaptive immunity. A healthy ate) potentially antigenic self molecules, cells, and adult contains 0.5 to 1 × 1012 lymphocytes. Although tissues. all lymphocytes are morphologically similar and rather unremarkable in appearance, they are heterogeneous CELLS OF THE ADAPTIVE IMMUNE in lineage, function, and phenotype and are capable SYSTEM of complex biologic responses and activities (Fig. 1.9). These cells often are distinguished by the expression This section of the chapter describes the important prop- of surface proteins that may be identified using panels erties of the major cell populations of adaptive immu- of monoclonal antibodies. The standard nomenclature nity—namely, lymphocytes and antigen-presenting cells for these proteins is the CD (cluster of differentiation)

Cell type Principal function(s)

Lymphocytes: Specific recognition of antigens B lymphocytes; and generation of adaptive immune responses: T lymphocytes • B lymphocytes: mediators of humoral immunity

Blood lymphocyte • T lymphocytes: mediators of cell-mediated immunity Antigen-presenting cells: Capture of antigens for display dendritic cells; to lymphocytes: macrophages; • Dendritic cells: initiation of T cell responses B cells; follicular dendritic cells • Macrophages: effector phase of cell-mediated immunity • Follicular dendritic cells: display of antigens to B lymphocytes in humoral immune responses Effector cells: Elimination of antigens: T lymphocytes; • T lymphocytes: activation of macrophages; phagocytes, killing infected cells • Macrophages: and killing of microbes Macrophage • Granulocytes: killing microbes Fig. 1.8 Principal cells of the adaptive immune system. Micrographs illustrate the morphology of some cells of each type. The major functions of these cell types are listed. 10 CHAPTER 1 Introduction to the Immune System

A Effector functions

Neutralization of microbe, B phagocytosis, lymphocyte complement Microbe activation Antibody

Cytokines Activation of macrophages

Inflammation Helper T lymphocyte

Microbial antigen Activation of presented by antigen B lymphocytes presenting cell

Cytotoxic T Killing of lymphocyte infected cell (CTL) Infected cell expressing microbial antigen

Suppression Regulatory of immune T lymphocyte response

Fig. 1.9 Classes of lymphocytes. A, Different classes of lymphocytes in the adaptive immune system rec- ognize distinct types of antigens and differentiate into effector cells whose function is to eliminate the anti- gens. B lymphocytes recognize soluble or microbial surface antigens and differentiate into antibody-secreting cells called plasma cells. Both helper T cells and cytotoxic T lymphocytes recognize peptides derived from intracellular microbial proteins displayed on the cell surface by MHC molecules, described in Chapter 3. Helper T cells recognize these peptides displayed on the surface of macrophages or other antigen presenting cells, and secrete cytokines that stimulate different mechanisms of immunity and inflammation. Cytotoxic T lymphocytes recognize peptides displayed by any type of infected cell type (or tumor cell), and kill these cells. Regulatory T cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity. CHAPTER 1 Introduction to the Immune System 11

B Class Functions Antigen Selected Percentage of and phenotypic total lymphocytes* specificity markers αβ T Lymphocytes

CD4+ B cell activation αβ heterodimers CD3+ Blood + helper T (humoral Diverse specificities CD4 node immunity) CD8– lymphocytes for peptide–class II 35–60 50–60 50–60 Macrophage MHC complexes activation (cell-mediated immunity) Stimulation of inflammation CD8+ Killing of cells αβ heterodimers CD3+ 15–40 15–20 10–15 infected with CD4– cytotoxic T Diverse specificities + lymphocytes intracellular for peptide–class I CD8 microbes, MHC complexes tumor cells Regulatory Suppress αβ heterodimers CD3+ 0.5–2 5–10 5–10 + T cells function of Specific for self CD4 other T cells CD25+ and some + (regulation foreign antigens FoxP3 of immune (peptide–class II (most common) responses, MHC complexes) maintenance of self-tolerance) B Lymphocytes

B cells Antibody Surface Ig Fc receptors Blood Lymph Spleen node production Diverse specificities class II MHC (humoral CD19 for many types 5–20 20–25 40–45 immunity) of molecules CD23

Fig. 1.9, cont’d B, The table summarizes the major properties of the lymphocytes of the adaptive immune system. Not included are γδ T cells, natural killer cells and other innate lymphoid cells, which are discussed in Chapter 2. *The percentages are approximations, based on data from human peripheral blood and mouse lymphoid organs. Ig, Immunoglobulin; MHC, major complex.

numeric designation, which is used to delineate surface membrane-bound antibodies that serve as the receptors proteins that define a particular cell type or stage of cell that recognize antigens and initiate the process of acti- differentiation and that are recognized by a cluster or vation of the cells. Soluble antigens and antigens on the group of antibodies. (A list of CD molecules mentioned surface of microbes and other cells may bind to these B in the book is provided in I.) lymphocyte antigen receptors, resulting in the prolifera- As alluded to earlier, B lymphocytes are the only cells tion and differentiation of the antigen-specific B cells. This capable of producing antibodies; therefore they are the leads to the of soluble forms of antibodies with cells that mediate humoral immunity. B cells express the same antigen specificity as the membrane receptors. 12 CHAPTER 1 Introduction to the Immune System

T lymphocytes are responsible for cell-mediated immu- When naive lymphocytes recognize microbial anti- nity. The antigen receptors of most T lymphocytes recog- gens and also receive additional signals induced by nize only peptide fragments of protein antigens that are microbes, the antigen-specific lymphocytes prolifer- bound to specialized peptide display molecules, called ate and then differentiate into effector cells and mem- major histocompatibility complex (MHC) molecules, on ory cells (Fig. 1.11). the surface of specialized cells, called antigen-presenting • Naive lymphocytes express receptors for antigens cells (see Chapter 3). Among T lymphocytes, CD4+ T cells but do not perform the functions that are required to are called helper T cells because they help B lymphocytes eliminate antigens. These cells reside in and circulate to produce antibodies and help phagocytes to destroy between peripheral lymphoid organs and survive for ingested microbes. CD8+ T lymphocytes are called cyto- several months up to a few years, waiting to find and toxic T lymphocytes (CTLs) because they kill cells harbor- respond to antigen. If they are not activated by anti- ing intracellular microbes. Some CD4+ T cells belong to a gen, naive lymphocytes die by the process of apopto- special subset that functions to prevent or limit immune sis and are replaced by new cells that have arisen in responses; these are called regulatory T lymphocytes. the generative lymphoid organs. The differentiation All lymphocytes arise from common lymphoid precur- of naive lymphocytes into effector cells and memory sor cells in the (Fig. 1.10). B lymphocytes cells is initiated by antigen recognition, thus ensuring mature in the bone marrow, and T lymphocytes mature that the immune response that develops is specific for in an organ called the . These sites in which mature the antigen that is recognized. lymphocytes are produced (generated) are called the gen- • Effector lymphocytes are the differentiated progeny erative (or central) lymphoid organs. Mature lympho- of naive cells that have the ability to produce molecules cytes leave the generative lymphoid organs and enter the that function to eliminate antigens. The effector cells circulation and peripheral (secondary) lymphoid organs, in the B lymphocyte lineage are antibody-secreting which are the major site of immune responses where cells, called plasma cells. Plasma cells develop in lymphocytes encounter antigens and are activated. response to antigenic stimulation in the peripheral

Generative Blood, Peripheral lymphoid lymph Mature, naive (secondary) organs B lymphocytes lymphoid organs Immature B lymphocytes

Bone Recirculation Common marrow Lymph lymphoid B nodes precursor lymphocyte lineage Spleen T lymphocyte Mucosal and lineage cutaneous lymphoid Recirculation tissues Bone Naive Marrow Thymus T lymphocytes Naive T lymphocytes Fig. 1.10 Maturation and tissue distribution of lymphocytes. Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). Mature lymphocytes enter the peripheral lym- phoid organs, where they respond to foreign antigens and recirculate in the blood and lymph. Some immature B cells leave the bone marrow and complete their maturation in the spleen (not shown). CHAPTER 1 Introduction to the Immune System 13

A Cell type Stage

Naive cell Activated or Memory effector lymphocyte lymphocyte B lymphocytes Antigen Proliferation Differentiation recognition

T lymphocytes Antigen Proliferation Differentiation recognition

B Naive cell Activated or Memory lymphocyte effector lymphocyte T lymphocytes Migration Preferentially Preferentially to Heterogenous: different to peripheral inflamed tissues subsets to lymph nodes, lymph nodes mucosa and other tissues Frequency of cells Very low High Low responsive to particular antigen Effector functions None secretion; None cytotoxic activity B lymphocytes Membrane IgM and IgD Frequently IgG, Frequently IgG, immunoglobulin IgA, and IgE (low level IgA, and IgE (Ig) in plasma cells) Affinity of Relatively low Increases during Relatively high Ig produced immune response Effector functions None Antibody secretion None Fig. 1.11 Stages in the life history of lymphocytes. A, Naive lymphocytes recognize foreign antigens to initiate adaptive immune responses. Naive lymphocytes need signals in addition to antigens to proliferate and differen- tiate into effector cells; these additional signals are not shown. Effector cells, which develop from naive cells, function to eliminate antigens. The effector cells of the B lymphocyte lineage are antibody-secreting plasma cells (some of which are long lived). The effector cells of the CD4 T lymphocyte lineage produce cytokines. (The effec- tor cells of the CD8 lineage are CTLs; these are not shown.) Other progeny of the antigen-stimulated lymphocytes differentiate into long-lived memory cells. B, The important characteristics of naive, effector, and memory cells in the B and T lymphocyte lineages are summarized. The generation and functions of effector cells, including changes in migration patterns and types of immunoglobulin produced, are described in later chapters. 14 CHAPTER 1 Introduction to the Immune System

lymphoid organs, where they may stay and produce which involutes after (seeChapter 4). Mem- antibodies. Small numbers of antibody-secreting cells ory cells are functionally inactive; they do not per- are also found in the blood; these are called plasma­ form effector functions unless stimulated by antigen. blasts. Some of these migrate to the bone marrow, When memory cells encounter the same antigen that where they mature into long-lived plasma cells and induced their development, the cells rapidly respond continue to produce antibody years after the infec- to initiate secondary immune responses. The signals tion is eradicated, providing immediate protection in that generate and maintain memory cells are not well case the infection recurs. understood but include cytokines. Effector CD4+ T cells (helper T cells) produce proteins called cytokines that activate B cells, mac- Antigen-Presenting Cells rophages, and other cell types, thereby mediating the The common portals of entry for microbes—the skin helper function of this lineage. The properties of cyto- and gastrointestinal, respiratory, and genitourinary kines are listed in Appendix II and will be discussed in tracts—contain specialized cells located in the epithe- later chapters. Effector CD8+ T cells (CTLs) have the lium that capture antigens, transport them to periph- machinery to kill infected host cells. The development eral lymphoid tissues, and display (present) them to and functions of these effector cells are also discussed lymphocytes. These are the first steps in the develop- in later chapters. Effector T lymphocytes are short ment of adaptive immune responses against antigens. lived and die as the antigen is eliminated. This function of antigen capture and presentation is • Memory cells, also generated from the progeny of best understood for dendritic cells, the most special- antigen-stimulated lymphocytes, can survive for long ized antigen-presenting cells (APCs) in the immune periods in the absence of antigen. Therefore the fre- system. Dendritic cells capture protein antigens of quency of memory cells increases with age, presum- microbes that cross epithelial barriers and transport ably because of exposure to environmental microbes. these antigens to regional lymph nodes, where they In fact, memory cells make up less than 5% of periph- display fragments of the proteins for recognition by T eral blood T cells in a newborn but 50% or more in lymphocytes. If a microbe has invaded through the epi- an adult (Fig. 1.12). As individuals age, the gradual thelium, it may be phagocytosed and presented by tis- accumulation of memory cells compensates for the sue macrophages. Microbes or their antigens that enter reduced output of new, naive T cells from the thymus, lymphoid organs may be captured by dendritic cells or macrophages that reside in these organs and presented to lymphocytes. The process of to Thymic output T cells is described in Chapter 3. Dendritic cells have another important feature that 100 gives them the ability to stimulate T cell responses. These 80 Naive T cells specialized cells respond to microbes by producing sur- Memory T cells face proteins, called costimulators, which are required, 60 together with antigen, to activate naive T lymphocytes to proliferate and differentiate into effector cells. Dendritic 40 cells express higher levels of these costimulatory proteins than do other cell types and are thus the most potent % Blood T cells 20 stimulators of naive T cells and the most efficient initi- 0 ators of T cell responses. Other antigen-presentingcells, 0 10 20 30 40 50 60 70 80 such as macrophages and B cells, present antigens to dif- Age (Years) ferentiated effector T cells in various immune responses. Fig. 1.12 Change in proportions of naive and memory B lymphocytes may directly recognize the anti- T cells with age. The proportions of naive and memory T gens of microbes (either released or on the surface of cells are based on data from multiple healthy individuals. The estimate of thymic output is an approximation. (Courtesy Dr. the microbes), and macrophages and dendritic cells in Donna L. Farber, Columbia University College of and peripheral lymphoid organs may also capture antigens Surgeons, New York, NY.) and display them to B cells. A distinct type of cell called CHAPTER 1 Introduction to the Immune System 15 the follicular dendritic cell (FDC) resides in the germi- Peripheral (Secondary) Lymphoid Organs and nal centers of lymphoid follicles in the peripheral lym- Tissues phoid organs and displays antigens that stimulate the The peripheral lymphoid organs and tissues, which differentiation of B cells in the follicles (seeChapter 7). consist of the lymph nodes, the spleen, and the muco- FDCs do not present antigens to T cells and differ from sal and cutaneous immune systems, are organized the dendritic cells described earlier that function as in a way that promotes the development of adaptive APCs for T lymphocytes. immune responses. T and B lymphocytes must locate microbes that enter at any site in the body, then respond to TISSUES OF THE IMMUNE SYSTEM these microbes and eliminate them. The anatomic orga- nization of peripheral lymphoid organs enables APCs to The tissues of the immune system consist of the gen- concentrate antigens in these organs and lymphocytes to erative lymphoid organs, in which T and B lympho- locate and respond to the antigens. This organization is cytes mature and become competent to respond to complemented by a remarkable ability of lymphocytes to antigens, and the peripheral lymphoid organs, in circulate throughout the body in such a way that naive which adaptive immune responses to microbes are lymphocytes preferentially go to the peripheral lymphoid initiated (see Fig. 1.10). Most of the lymphocytes in organs and tissues, in which antigen is concentrated, a healthy human are found in lymphoid organs and whereas most effector cells go to sites of infection where other tissues (Fig. 1.13). However, as we discuss later, microbes must be eliminated. Furthermore, different lymphocytes are unique among the cells of the body types of lymphocytes often need to communicate to gen- because of their ability to recirculate, repeatedly going erate effective immune responses. For example, within through the blood to visit every secondary lymphoid peripheral lymphoid organs, helper T cells specific for an organ in the body. The generative (also called primary antigen interact with and help B lymphocytes specific for or central) lymphoid organs are described in Chapter the same antigen, resulting in antibody production. An 4, when we discuss the process of lymphocyte matu- important function of lymphoid organs is to bring these ration. The following section highlights some of the rare cells together after stimulation by antigen so they features of peripheral (or secondary) lymphoid organs interact when they need to. that are important for the development of adaptive The major peripheral lymphoid organs share many immunity. characteristics but also have some unique features. • Lymph nodes are encapsulated nodular aggregates of lymphoid tissues located along lymphatic channels Tissue Number of throughout the body (Fig. 1.14). Fluid constantly lymphocytes leaks out of small blood vessels in all epithelia and connective tissues and most parenchymal organs. 9 Spleen 70 x 10 This fluid, called lymph, is drained by lymphatic ves- Lymph nodes 190 x 109 sels from the tissues to the lymph nodes and even- tually back into the blood circulation. Therefore the Bone marrow 50 x 109 lymph contains a mixture of substances absorbed Blood 10 x 109 from epithelia and tissues. As the lymph passes through lymph nodes, APCs in the nodes are able Skin 20 x 109 to sample the antigens of microbes that may enter through epithelia into tissues. In addition, dendritic 50 x 109 Intestines cells pick up antigens of microbes from epithelia 10 x 109 and other tissues and transport these antigens to the lymph nodes. The net result of these processes 9 30 x 10 of antigen capture and transport is that the antigens Fig. 1.13 Distribution of lymphocytes in lymphoid organs of microbes entering through epithelia or coloniz- and other tissues. Approximate numbers of lymphocytes in ing tissues become concentrated in draining lymph different organs of healthy adults are shown. nodes. 16 CHAPTER 1 Introduction to the Immune System

A A Marginal Antigen sinus B cell zone High Follicular (follicle) endothelial arteriole (HEV) Afferent B cell zone Subcapsular lymphatic (follicle) sinus vessel T cell zone (periarteriolar lymphoid sheath PALS) Trabecular Central Marginal arteriole zone B

T cell zone Capsule Germinal Medulla center Medullary Artery sinus Efferent Lymphocytes B Primary lymphoid Germinal follicle (B cell zone) Periarteriolar center of lymphoid lymphoid sheath (PALS) follicle

Fig. 1.15 Morphology of the spleen. A, Schematic diagram shows a splenic arteriole surrounded by the periarteriolar lymphoid sheath (PALS) and attached follicles. The PALS and lymphoid follicles together constitute the . The with its sinus is the indistinct boundary between the white pulp and the red pulp. B, Light micro- graph of a section of spleen shows an arteriole with the PALS and a follicle with a prominent . These are surrounded by the red pulp, which is rich in vascular sinusoids. Secondary Parafollicular follicle with (T cell zone) germinal center responses to lymph-borne antigens (Fig. 1.15). Fig. 1.14 Morphology of lymph nodes. A, Schematic dia- gram shows the structural organization of a . Blood entering the spleen flows through a network B, Light micrograph shows a cross section of a lymph node of channels (sinusoids). Blood-borne antigens are with numerous follicles in the cortex, some of which contain captured and concentrated by dendritic cells and lightly stained central areas (germinal centers). macrophages in the spleen. The spleen contains abundant phagocytes that line the sinusoids, which • The spleen is a highly vascularized abdominal organ ingest and destroy microbes in the blood. These that serves the same role in immune responses to macrophages also ingest and destroy old red blood blood-borne antigens as that of lymph nodes in cells. CHAPTER 1 Introduction to the Immune System 17

Villus Commensal

Intraepithelial lymphocytes Intestinal Intestinal M cell lumen epithelial cell

Dendritic cell Peyer’s Mucosal Afferent Crypt patch lymphatic IgA Lymphatic drainage Follicle

B cell Dendritic T cell cell Macrophage

Mesentery Mesenteric lymph node

Fig. 1.16 Mucosal immune system. Schematic diagram of the mucosal immune system uses the small bowel as an example. Many commensal bacteria are present in the lumen. The mucus-secreting epi- thelium provides an innate barrier to microbial invasion (discussed in Chapter 2). Specialized epithelial cells, such as M cells, promote the transport of antigens from the lumen into underlying tissues. Cells in the lamina propria, including dendritic cells, T lymphocytes, and macrophages, provide innate and adaptive immune defense against invading microbes; some of these cells are organized into specialized structures, such as Peyer patches in the . (IgA) is a type of antibody abundantly produced in mucosal tissues that is transported into the lumen, where it binds and neutralizes microbes (see Chapter 8).

• The cutaneous immune system and mucosal example, in the and Peyer patches immune system are specialized collections of lym- in the intestine are two anatomically defined phoid tissues and APCs located in and under the mucosal lymphoid tissues (Fig. 1.16). The immune epithelia of the skin and the gastrointestinal and system of the skin consists of most of the cells of respiratory tracts, respectively. Although most innate and adaptive immunity, but without any of the immune cells in these tissues are diffusely anatomically defined structures (Fig. 1.17). At any scattered beneath the epithelial barriers, there time, at least a quarter of the body’s lymphocytes are discrete collections of lymphocytes and APCs are in the mucosal tissues and skin (reflecting the organized in a similar way as in lymph nodes. For large size of these tissues) (see Fig. 1.13), and many 18 CHAPTER 1 Introduction to the Immune System

Commensal and pathogenic microbes

Keratinocytes Epidermal

Epidermis Intraepithelial lymphocyte (CD8+) Basal Plasma cell Postcapillary

Dermis Lymphatic venule vessel Macrophage

T lymphocyte (CD4+) Drainage to regional lymph node Dermal dendritic cell

Fig. 1.17 Cutaneous immune system. The major components of the cutaneous immune system shown in this schematic diagram include keratinocytes, Langerhans cells, and intraepithelial lymphocytes, all located in the , and T lymphocytes, dendritic cells, and macrophages, located in the .

of these are memory cells. Cutaneous and mucosal center. The germinal center has an important role in lymphoid tissues are sites of immune responses to the production of highly effective antibodies and is antigens that breach epithelia. A remarkable prop- described in Chapter 7. The T lymphocytes are con- erty of the cutaneous and mucosal immune sys- centrated outside but adjacent to the follicles, in the tems is that they are able to respond to pathogens paracortex. The follicles contain the FDCs described but do not react to the enormous numbers of usu- earlier that are involved in the activation of B cells, ally harmless commensal microbes present at the and the paracortex contains dendritic cells that pres- epithelial barriers. This is accomplished by several ent antigens to T lymphocytes. In the spleen, T lym- mechanisms, including the action of regulatory T phocytes are concentrated in periarteriolar lymphoid cells and other cells that suppress rather than acti- sheaths surrounding small arterioles, and B cells reside vate T lymphocytes. in the follicles. Within the peripheral lymphoid organs, T lym- The anatomic organization of peripheral lymphoid phocytes and B lymphocytes are segregated into dif- organs is tightly regulated to allow immune responses ferent anatomic compartments (Fig. 1.18). In lymph to develop after stimulation by antigens. B lymphocytes nodes, the B cells are concentrated in discrete struc- are attracted to and retained in the follicles because of tures, called follicles, located around the periphery, or the action of a class of cytokines called cortex, of each node. If the B cells in a follicle have (chemoattractant cytokines; chemokines and other recently responded to a protein antigen and received cytokines are discussed in more detail in later chapters). signals from helper T cells, this follicle may contain FDCs in the follicles secrete a particular for a central lightly staining region called a germinal which naive B cells express a receptor, called CXCR5. CHAPTER 1 Introduction to the Immune System 19

A

Dendritic cell Naive High B cell B cell–specific endothelial chemokine venule B

Afferent lymphatic vessel T cell zone (parafollicular cortex)

B cell B cell zone zone (lymphoid T cell follicle) Artery zone B cell T cell and dendritic cell–specific chemokine T cell Fig. 1.18 Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. A, Schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas of a lymph node. Naive B and T lymphocytes enter through a high endothelial venule (HEV), shown in cross section, and are drawn to different areas of the node by chemokines that are produced in these areas and bind selec- tively to either cell type. Also shown is the migration of dendritic cells, which pick up antigens from epithelia, enter through afferent lymphatic vessels, and migrate to the T cell–rich areas of the node (see Chapter 3). B, In this histologic section of a lymph node, the B lymphocytes, located in the follicles, are stained green, and the T cells, in the parafollicular cortex, are stained red using immunofluorescence. In this technique, a section of the tissue is stained with antibodies specific for T or B cells coupled to fluorochromes that emit different colors when excited at the appropriate wavelengths. The anatomic segregation of T and B cells also occurs in the spleen (not shown). (Courtesy Drs. Kathryn Pape and Jennifer Walter, University of Minnesota , Minneapolis, MN.)

The chemokine that binds to CXCR5 attracts B cells ferentiate into antibody-producing cells (see Chapter 7). from the blood into the follicles of lymphoid organs. Thus, these lymphocyte populations are kept apart from Similarly, T cells are segregated in the paracortex of each other until it is useful for them to interact, after lymph nodes and the periarteriolar lymphoid sheaths of exposure to an antigen. This is an excellent example of the spleen because naive T lymphocytes express a recep- how the structure of lymphoid organs ensures that the tor, called CCR7, which recognizes chemokines that cells that have recognized and responded to an antigen are produced in these regions of the lymph nodes and interact and communicate with one another only when spleen. When the lymphocytes are activated by antigens, necessary. they alter their expression of chemokine receptors. As a Many of the effector T cells exit the node through result, the antigen-activated B cells and T cells migrate efferent lymphatic vessels and leave the spleen through toward each other and meet at the edge of follicles, . These activated lymphocytes end up in the where helper T cells interact with and help B cells to dif- circulation and can go to distant sites of infection. 20 CHAPTER 1 Introduction to the Immune System

Some activated T cells remain in the lymphoid organ The migration of different lymphocyte popula- where they were generated and migrate into lymphoid tions has distinct features and is controlled by different follicles, where they help B cells to make high-affinity molecular interactions. antibodies. • Naive T lymphocytes that have matured in the thy- mus and entered the circulation migrate to lymph Lymphocyte Recirculation and Migration into nodes, where they can find antigens that are brought Tissues to the lymph nodes through lymphatic vessels that Naive lymphocytes constantly recirculate between drain epithelia and parenchymal organs. These the blood and peripheral lymphoid organs, where naive T cells enter lymph nodes through special- they may be activated by antigens to become effec- ized postcapillary , called high endothelial tor cells, and the effector lymphocytes migrate venules (HEVs). The adhesion molecules used by the from lymphoid tissues to sites of infection, where T cells to bind to the are described in microbes are eliminated (Fig. 1.19). Thus, lympho- Chapter 5. Chemokines produced in the T cell zones cytes at distinct stages of their migrate to the of the lymph nodes and displayed on HEV surfaces different sites where they are needed for their func- bind to the chemokine receptor CCR7 expressed on tions. Migration of effector lymphocytes to sites of naive T cells, which causes the T cells to bind tightly infection is most relevant for T cells because effector to HEVs. The naive T cells then migrate into the T T cells have to locate and eliminate microbes at these cell zone, where antigens are displayed by dendritic sites. By contrast, plasma cells do not need to migrate cells. Naive B cells also enter lymphoid tissues but to sites of infection; instead, they secrete antibodies, then migrate to follicles in response to chemokines and the antibodies enter the blood. These antibodies that bind CXCR5, the chemokine receptor expressed bind pathogens or toxins in the blood, or in tissues on these B cells. into which the antibodies enter. Plasma cells in muco- • In the lymph node, T cells move around rapidly, sal organs secrete antibodies that enter the lumens of scanning the surfaces of dendritic cells for antigens. these organs, where they bind to and combat ingested If a T cell specifically recognizes an antigen on a den- and inhaled microbes. dritic cell, that T cell forms stable conjugates with

Chemokines Lymph node Peripheral tissue High endothelial venule Peripheral Blood Artery vessel

Effector or Efferent lymphatic vessel Naive T cell

Fig. 1.19 Migration of T lymphocytes. Naive T lymphocytes migrate from the blood through high endothe- lial venules into the T cell zones of lymph nodes, where the cells are activated by antigens. Activated T cells exit the nodes, enter the bloodstream, and migrate preferentially to peripheral tissues at sites of infection and inflammation. The adhesion molecules involved in the attachment of T cells to endothelial cells are described in Chapters 5 and 6. CHAPTER 1 Introduction to the Immune System 21

the dendritic cell and is activated. Such an encounter control these precise patterns of migration of naive between an antigen and a specific lymphocyte is likely and activated T cells (see Chapter 6). to be a random event, but most T cells in the body • B lymphocytes that recognize and respond to antigen circulate through some lymph nodes at least once a in lymph node follicles differentiate into antibody-­ day. As mentioned earlier and described further in secreting plasma cells, most of which migrate to the Chapter 3, the likelihood of the correct T cell find- bone marrow or mucosal tissues (see Chapter 7). ing its antigen is increased in peripheral lymphoid • Memory T cells consist of different populations (see organs, particularly lymph nodes, because micro- Chapter 6); some cells recirculate through lymph bial antigens are concentrated in the same regions of nodes, where they can mount secondary responses these organs through which naive T cells circulate. to captured antigens, and other cells migrate to sites Thus, T cells find the antigen they can recognize, and of infection, where they can respond rapidly to elim- these T cells are activated to proliferate and differen- inate the infection. Yet other memory cells perma- tiate. Naive cells that have not encountered specific nently reside in epithelial tissues, such as mucosal antigens leave the lymph nodes and reenter the cir- tissues and the skin. culation. We know less about lymphocyte circulation through • The effector cells that are generated upon T cell acti- the spleen or other lymphoid tissues. The spleen does vation preferentially migrate into the tissues infected not contain HEVs, but the general pattern of naive lym- by microbes, where the T lymphocytes perform their phocyte migration through this organ probably is simi- function of eradicating the infection. Specific signals lar to migration through lymph nodes.

SUMMARY • The physiologic function of the immune system is to • B lymphocytes are the only cells that produce anti- protect individuals against infections and cancers. bodies. B lymphocytes express membrane antibodies • Innate immunity is the early line of defense, medi- that recognize antigens, and the progeny of activated ated by cells and molecules that are always present B cells, called plasma cells, secrete the antibodies that and ready to eliminate infectious microbes. neutralize and eliminate the antigen. • Adaptive immunity is mediated by lymphocytes stim- • T lymphocytes recognize peptide fragments of pro- ulated by microbial antigens, which leads to the pro- tein antigens displayed on other cells. Helper T lym- liferation and differentiation of the lymphocytes and phocytes produce cytokines that activate phagocytes generation of effector cells, and responds more effec- to destroy ingested microbes, recruit leukocytes, and tively against each successive exposure to a microbe. activate B lymphocytes to produce antibodies. Cyto- • Lymphocytes are the cells of adaptive immunity and toxic T lymphocytes (CTLs) kill infected cells har- are the only cells with clonally distributed receptors boring microbes in the cytoplasm. specific for different antigens. • Antigen-presenting cells (APCs) capture antigens of • Adaptive immunity consists of humoral immunity, in microbes that enter through epithelia, concentrate which antibodies neutralize and eradicate extracellular these antigens in lymphoid organs, and display the microbes and toxins, and cell-mediated immunity, in antigens for recognition by T cells. which T lymphocytes eradicate intracellular microbes. • Lymphocytes and APCs are organized in periph- • Adaptive immune responses consist of sequential eral (secondary) lymphoid organs, where immune phases: antigen recognition by lymphocytes, activa- responses are initiated and develop. tion of the lymphocytes to proliferate and to differ- • Naive lymphocytes circulate through peripheral lym- entiate into effector and memory cells, elimination of phoid organs, searching for foreign antigens. Effector the microbes, decline of the immune response, and T lymphocytes migrate to peripheral sites of infection, long-lived memory. where they function to eliminate infectious microbes. • Different populations of lymphocytes serve distinct Plasma cells remain in lymphoid organs and the bone functions and may be distinguished by the surface marrow, where they secrete antibodies that enter the expression of particular membrane molecules. circulation and find and eliminate microbes. 22 CHAPTER 1 Introduction to the Immune System

REVIEW QUESTIONS 1. What are the two types of adaptive immunity, and 4. Where are T and B lymphocytes located in lymph what types of microbes do these adaptive immune nodes, and how is their anatomic separation main- responses combat? tained? 2. What are the principal classes of lymphocytes, and 5. How do naive and effector T lymphocytes differ in how do they differ in function? their patterns of migration? 3. What are the important differences among naive, effector, and memory T and B lymphocytes?

Answers to and discussion of the Review Questions are available at Student Consult.