med 2

growth factor beta (TGF-ß) are cytokines of both innate and adaptive immunity (see Chapters 5 and 6). More information about these cytokines and their receptors is provided in Appendix II. MHC, Major histocompatibility complex.

CHAPTER 2 Innate Immunity 43

• Intracellular bacteria, which can survive inside

phagocytes, are eliminated by phagocytes that are

activated by Toll-like receptors and other innate sensors as well as by cytokines.

• Protection against viruses is provided by type I interferons and natural killer cells.

Inflammation

Inflammation is a tissue reaction that delivers mediators of host defense—circulating cells and proteins—

to sites of infection and tissue damage (Fig. 2.16). The

process of inflammation consists of recruitment of cells

and leakage of plasma proteins through blood vessels

and activation of these cells and proteins in the extravascular tissues. The initial release of histamine, TNF,

prostaglandins, and other mediators by mast cells and

macrophages causes an increase in local blood flow and

exudation of plasma proteins. These contribute to redness, warmth, and swelling, which are characteristic features of inflammation. This is often followed by a local

accumulation in the tissue of phagocytes, mainly neutrophils and blood monocyte-derived macrophages, in

response to cytokines, discussed below. Activated phagocytes engulf microbes and necrotic material and destroy

these potentially harmful substances. We next describe

the cellular events in a typical inflammatory response.

4 5

Injury, barrier break,

microbe entry

Microbes/injury

activate sentinel cells

Sentinel cells secrete

inflammatory mediators

Increased vascular

permeability; fluid and

proteins enter tissues

Complement, antibodies,

and anti–microbial proteins

Fig. 2.16 Acute inflammatory response. Cytokines and other mediators are produced by macrophages,

dendritic cells, mast cells, and other cells in tissues in response to microbial products and damaged host cells.

Some of these mediators (e.g., histamine, prostaglandins) increase the permeability of blood vessels, leading

to the entry of plasma proteins (e.g., complement proteins) into the tissues, and others (IL-1, TNF) increase

expression of endothelial adhesion molecules and chemokines that promote the movement of leukocytes

from the blood into the tissues, where the leukocytes destroy microbes, clear damaged cells, and promote

more inflammation and repair.

44 CHAPTER 2 Innate Immunity

Recruitment of Phagocytes to Sites of Infection and

Tissue Damage

Neutrophils and monocytes migrate to extravascular

sites of infection or tissue damage by binding to venular endothelial adhesion molecules and in response

to chemoattractants produced by tissue cells reacting

to infection or injury. Leukocyte migration from the

blood into tissues is a multistep process in which initial weak adhesive interactions of the leukocytes with

endothelial cells are followed by firm adhesion and then

transmigration through the endothelium (Fig. 2.17).

If an infectious microbe breaches an epithelium and

enters the subepithelial tissue, resident dendritic cells,

macrophages, and other cells recognize the microbe

and respond by producing cytokines. Two of these cytokines, TNF and IL-1, act on the endothelium of venules

near the site of infection and initiate the sequence of

events in leukocyte migration into tissues.

• Rolling of leukocytes. In response to TNF and IL-1,

venular endothelial cells express an adhesion molecule of the selectin family called E-selectin. Other

stimuli, including thrombin, cause rapid translocation of P-selectin to the endothelial surface. (The

term selectin refers to the carbohydrate-binding,

or lectin, property of these molecules.) Circulating

neutrophils and monocytes express surface carbohydrates that bind specifically to the selectins. The

neutrophils become tethered to the endothelium,

flowing blood disrupts this binding, the bonds

reform downstream, and this repetitive process

results in the rolling of the leukocytes along the

endothelial surface.

• Firm adhesion. Leukocytes express another set of

adhesion molecules that are called integrins because

they integrate extrinsic signals into cytoskeletal

alterations. Leukocyte integrins, such as LFA-1 and

Chemokines

Fibrin and fibronectin

(extracellular matrix)

Macrophage stimulated

by microbes

Rolling Integrin activation

Integrin (highaffinity state)

Chemokines

Fig. 2.17 Sequence of events in migration of blood leukocytes to sites of infection. At sites of infection,

macrophages, dendritic cells, and other cells that have encountered microbes produce cytokines such as

tumor necrosis factor (TNF) and interleukin-1 (IL-1) that activate the endothelial cells of nearby venules to

express selectins and ligands for integrins and to secrete chemokines. Selectins mediate weak tethering and

rolling of blood neutrophils on the endothelium, integrins mediate firm adhesion of neutrophils, and chemokines activate the neutrophils and stimulate their migration through the endothelium to the site of infection.

Blood monocytes and activated T lymphocytes use the same mechanisms to migrate to sites of infection.

CHAPTER 2 Innate Immunity 45

VLA-4, are present in a low-affinity state on unactivated cells. Within a site of infection, tissue macrophages and endothelial cells produce chemokines,

which bind to proteoglycans on the luminal surface

of endothelial cells and are thus displayed at a high

concentration to the leukocytes that are rolling on

the endothelium. These immobilized chemokines

bind to chemokine receptors on the leukocytes and

stimulate a rapid increase in the affinity of the leukocyte integrins for their ligands on the endothelium.

Concurrently, TNF and IL-1 act on the endothelium to stimulate expression of ligands for integrins,

including ICAM-1 and VCAM-1. The firm binding

of integrins to their ligands arrests the rolling leukocytes on the endothelium. The cytoskeleton of the

leukocytes is reorganized, and the cells spread out on

the endothelial surface.

• Leukocyte migration. Leukocytes adherent to the

endothelium crawl to and then through the junctions between endothelial cells, exiting the blood

vessels. Within the tissue, leukocytes migrate along

extracellular matrix fibers, directed by concentration

gradients of chemoattractants, including chemokines, bacterial formyl peptides, and complement

fragments C5a and C3a. The concentrations of these

chemoattractants are highest where the microbes are

located, and leukocytes have receptors for these molecules that stimulate migration toward their source.

The sequence of selectin-mediated rolling, integrin-mediated firm adhesion, and chemokine-mediated

motility leads to the migration of blood leukocytes to an

extravascular site of infection within minutes after the

infection. (As discussed in Chapters 5 and 6, the same

sequence of events is responsible for the migration of

activated T lymphocytes into infected tissues.) Inherited deficiencies in integrins and selectin ligands lead to

defective leukocyte recruitment to sites of infection and

increased susceptibility to infections. These disorders

are called leukocyte adhesion deficiencies (LADs).

The phagocytes work together with plasma proteins

that have entered the site of inflammation, such as complement proteins, to destroy the offending agents. In some

infections, blood leukocytes other than neutrophils and

macrophages, such as eosinophils, may be recruited to sites

of infection and provide defense against the pathogens.

Phagocytosis and Destruction of Microbes

Neutrophils and macrophages ingest (phagocytose) microbes and destroy the ingested microbes in

intracellular vesicles (Fig. 2.18). Phagocytosis is a process of ingestion of particles larger than 0.5 µm in diameter. It begins with membrane receptors binding to the

microbe. The principal phagocytic receptors are some

pattern recognition receptors, such as mannose receptors and other lectins, and receptors for antibodies and

complement. Microbes opsonized with antibodies and

complement fragments can bind avidly to specific receptors on phagocytes, resulting in greatly enhanced internalization (see Chapter 8). Binding of the microbe to the

cell is followed by extension of the phagocyte plasma

membrane around the particle. The membrane then

closes up and pinches off, and the microbe is internalized in a membrane-bound vesicle, called a phagosome.

The phagosomes fuse with lysosomes to form phagolysosomes.

At the same time that the microbe is being bound by

the phagocyte’s receptors and ingested, the phagocyte

receives signals from various receptors that activate several enzymes. One of these enzymes, called phagocyte

oxidase, rapidly assembles in the phagolysomal membrane, mainly in neutrophils, and converts molecular

oxygen into superoxide anion and free radicals, a process called the oxidative burst (or respiratory burst).

These free radicals are called reactive oxygen species

(ROS) and are toxic to the ingested microbes. A second enzyme, inducible nitric oxide synthase (iNOS), is

produced mainly in macrophages and catalyzes the conversion of arginine to nitric oxide (NO), also a microbicidal substance. A third set of enzymes, the lysosomal

proteases, break down microbial proteins. All these

microbicidal substances are produced mainly within

lysosomes and phagolysosomes, where they act on the

ingested microbes but do not damage the phagocytes.

In addition to intracellular killing, neutrophils use

additional mechanisms to destroy microbes. They can

release microbicidal granule contents into the extracellular environment. In response to pathogens and

inflammatory mediators, neutrophils die, and during

this process they extrude their nuclear contents to form

networks of chromatin called neutrophil extracellular

traps (NETs), which contain antimicrobial substances

that are normally sequestered in neutrophil granules.

These NETs trap bacteria and fungi and kill the organisms. In some cases, the enzymes and ROS that are liberated into the extracellular space may injure host tissues.

This is the reason why inflammation, normally a protective host response to infections, may cause tissue injury

as well.

46 CHAPTER 2 Innate Immunity

Inherited deficiency of the phagocyte oxidase enzyme

is the cause of an immunodeficiency disorder called

chronic granulomatous disease (CGD). In CGD,

neutrophils are unable to eradicate intracellular microbes,

and the host tries to contain the infection by calling in

more macrophages, resulting in collections of activated

macrophages around the microbes called granulomas.

Tissue Repair

In addition to eliminating pathogenic microbes and

damaged cells, cells of the immune system initiate the

process of tissue repair. Macrophages, especially of the

alternatively activated type, produce growth factors that

stimulate the proliferation of residual tissue cells and

fibroblasts, resulting in regeneration of the tissue and

scarring of what cannot be replaced. Other immune cells,

such as helper T cells and ILCs, may serve similar roles.

Antiviral Defense

Defense against viruses is a special type of host response

that involves interferons, NK cells, and other mechanisms, which may occur concomitantly with, but are

distinct from, inflammation.

Type I interferons inhibit viral replication and

induce an antiviral state, in which cells become resistant to infection. Type I IFNs, which include several

forms of IFN-a and one of IFN-ß, are secreted by many

cell types infected by viruses. A major source of these

cytokines is a type of dendritic cell called the plasmacytoid dendritic cell (so named because these cells morphologically resemble plasma cells), which secretes type

I IFNs in response to recognition of viral nucleic acids

by TLRs and other pattern recognition receptors. When

type I IFNs secreted from dendritic cells or other infected

cells bind to the type I IFN receptor on the infected or

adjacent uninfected cells, signaling pathways are activated that inhibit viral replication and destroy viral

genomes (Fig. 2.19). This action is the basis for the use

of IFN-a to treat some forms of chronic viral hepatitis.

Virus-infected cells may be destroyed by NK cells, as

described earlier. Type I IFNs enhance the ability of NK

cells to kill infected cells. Recognition of viral DNA by

CDSs also induces autophagy, by which cellular organelles containing viruses are engulfed by lysosomes and

proteolytically destroyed (see Fig. 2.6). In addition,

part of the innate response to viral infections includes

increased apoptosis of infected cells, which also helps to

eliminate the reservoir of infection.

Regulation of Innate Immune Responses

Innate immune responses are regulated by a variety of mechanisms that are designed to prevent

Fig. 2.18 Phagocytosis and intracellular killing of microbes.

Macrophages and neutrophils express many surface receptors

that may bind microbes for subsequent phagocytosis; select

examples of such receptors are shown. Microbes are ingested

into phagosomes, which fuse with lysosomes, and the

microbes are killed by enzymes and several toxic substances

produced in the phagolysosomes. The same substances may

be released from the phagocytes and may kill extracellular

microbes (not shown). iNOS, Inducible nitric oxide synthase;

NO, nitric oxide; ROS, reactive oxygen species.

CHAPTER 2 Innate Immunity 47

excessive damage to tissues. These regulatory mechanisms include the production of antiinflammatory cytokines by macrophages and dendritic cells,

including interleukin-10 (IL-10), which inhibits

the microbicidal and proinflammatory functions of

macrophages (classical pathway of macrophage activation), and IL-1 receptor antagonist, which blocks

the actions of IL-1. There are also many feedback

mechanisms in which signals that induce proinflammatory cytokine production also induce expression

of inhibitors of cytokine signaling. For example, TLR

signaling stimulates expression of proteins called suppressors of cytokine signaling (SOCS), which block

the responses of cells to various cytokines, including

IFNs. Intracellular regulators of inflammasome activation were mentioned earlier.

Microbial Evasion of Innate Immunity

Pathogenic microbes have evolved to resist the mechanisms of innate immunity and are thus able to enter

and colonize their hosts (Fig. 2.20). Some intracellular bacteria resist destruction inside phagocytes.

Listeria monocytogenes produces a protein that

enables it to escape from phagocytic vesicles and

enter the cytoplasm of infected cells, where it is no

longer susceptible to ROS or NO (which are produced mainly in phagolysosomes). The cell walls

of mycobacteria contain a lipid that inhibits fusion

of phagosomes containing ingested bacteria with

lysosomes. Other microbes have cell walls that are

resistant to the actions of complement proteins. As

discussed in Chapters 6 and 8, these mechanisms also

enable microbes to resist the effector mechanisms of

cell-mediated and humoral immunity, the two arms

of adaptive immunity.

ROLE OF INNATE IMMUNITY IN

STIMULATING ADAPTIVE IMMUNE

RESPONSES

So far we have focused on how the innate immune

system recognizes microbes and combats infections.

We mentioned at the beginning of this chapter that, in

addition to its roles in host defense, the innate immune

response to microbes serves an important warning function by alerting the adaptive immune system that an

effective immune response is needed. In this final section, we summarize some of the mechanisms by which

innate immune responses stimulate adaptive immune

responses.

Innate immune responses generate molecules

that provide signals, in addition to antigens, that

are required to activate naive T and B lymphocytes.

In Chapter 1, we introduced the concept that full

IFNs induce enzymes that

block viral replication

Fig. 2.19 Antiviral actions of type I interferons. Type I interferons (IFN-a, IFN-ß) are produced by plasmacytoid dendritic

cells and virus-infected cells in response to intracellular TLR

signaling and other sensors of viral nucleic acids. Type I interferons bind to receptors on the infected and uninfected cells

and activate signaling pathways that induce expression of

enzymes that interfere with viral replication at different steps,

including inhibition of viral protein translation, increasing viral

RNA degradation, and inhibition of viral gene expression and

virion assembly. Type I IFNs also increase the infected cell’s

susceptibility to CTL-mediated killing (not shown).

48 CHAPTER 2 Innate Immunity

activation of antigen-specific lymphocytes requires

two signals. Antigen may be referred to as signal 1,

and innate immune responses to microbes and to host

cells damaged by microbes may provide signal 2 (Fig.

2.21). The stimuli that warn the adaptive immune

system that it needs to respond have also been called

danger signals. This requirement for microbe-dependent second signals ensures that lymphocytes

respond to infectious agents and not to harmless,

noninfectious substances. In experimental situations or for vaccination, adaptive immune responses

may be induced by antigens without microbes. In all

such instances, the antigens need to be administered

with substances called adjuvants that elicit the same

innate immune reactions as microbes do. In fact,

many potent adjuvants are the products of microbes.

The nature and mechanisms of action of second signals are described in the discussion of the activation of T and B lymphocytes in Chapters 5 and 7,

respectively. Here we describe two illustrative examples of second signals that are generated during innate

immune reactions.

In infected tissues, microbes (or IFN-? produced by

NK cells in response to microbes) stimulate dendritic

cells and macrophages to produce two types of second

signals that can activate T lymphocytes. First, dendritic cells increase their expression of surface molecules called costimulators, which bind to receptors on

Fig. 2.21 Two-signal requirement for lymphocyte activation. Antigen recognition by lymphocytes provides signal 1 for

activation of the lymphocytes, and substances produced during

innate immune responses to microbes (or components of

microbes) provide signal 2. In this illustration, the lymphocytes

could be T cells or B cells. By convention, the major second

signals for T cells are called costimulators because they function together with antigens to stimulate the cells. The nature of

second signals for T and B lymphocytes is described further in

later chapters.

Resistance to phagocytosis

Resistance to reactive oxygen

intermediates in phagocytes

Resistance to complement

activation (alternative pathway)

Capsular polysaccharide

inhibits phagocytosis

Production of catalase, which

breaks down reactive oxygen

intermediates

Sialic acid expression inhibits

C3 and C5 convertases

M protein blocks C3 binding to

organism, and C3b binding to

complement receptors

Pneumococci

Staphylococci

Neisseria meningitidis

Streptococci

Pseudomonas Synthesis of modified LPS

that resists action of

anti-bacterial peptides

Mechanism of immune evasion Organism (example) Mechanism

Resistance to antimicrobial

peptide antibiotics

Fig. 2.20 Evasion of innate immunity by microbes. Selected examples of the mechanisms by which

microbes may evade or resist innate immunity. LPS, Lipopolysaccharide.

CHAPTER 2 Innate Immunity 49

naive T cells and function together with antigen recognition to activate the T cells. Second, the dendritic

cells and macrophages secrete cytokines such as IL-12,

IL-1, and IL-6, which stimulate the differentiation of

naive T cells into effector cells of cell-mediated adaptive immunity.

Blood-borne microbes activate the complement

system by the alternative pathway. One of the proteins

produced during complement activation by proteolysis

of C3b, called C3d, becomes covalently attached to the

microbe. At the same time that B lymphocytes recognize

microbial antigens by their antigen receptors, the B cells

recognize the C3d bound to the microbe by a receptor

for C3d. The combination of antigen recognition and

C3d recognition initiates the process of B cell differentiation into antibody-secreting cells. Thus, a complement product serves as the second signal for humoral

immune responses.

These examples illustrate an important feature of

second signals: these signals not only stimulate adaptive

immunity, but they also guide the nature of the adaptive immune response. Intracellular and phagocytosed

microbes need to be eliminated by cell-mediated immunity, the adaptive response mediated by T lymphocytes.

Microbes that are encountered and ingested by dendritic cells or macrophages induce the second signals—

that is, costimulators and cytokines—that stimulate T

cell responses. By contrast, blood-borne microbes need

to be combated by antibodies, which are produced by

B lymphocytes during humoral immune responses.

Blood-borne microbes activate the plasma complement

system, which in turn stimulates B cell activation and

antibody production. Thus, different types of microbes

induce innate immune responses that stimulate the

types of adaptive immunity that are best able to combat

different infectious pathogens.

SUMMARY

• All multicellular organisms have intrinsic mechanisms of defense against infections, which constitute

innate immunity.

• The innate immune system uses germline-encoded

receptors to respond to structures that are characteristic of various classes of microbes and also recognizes

products of dead cells. Innate immune reactions usually are not enhanced by repeat exposures to microbes.

• Toll-like receptors (TLRs), expressed on plasma

membranes and endosomal membranes of many

cell types, are a major class of innate immune system

receptors that recognize different microbial products,

including bacterial cell wall constituents and microbial nucleic acids. Some cytosolic receptors of the

NOD-like receptor (NLR) family recognize microbial cell wall lipoproteins, while other NLRs respond

to products of damaged cells and cytosolic changes

typical of infection or cell injury, forming a multiprotein complex, the inflammasome, that generates the

active form the proinflammatory cytokine interleukin-1 (IL-1).

• The principal components of innate immunity are:

epithelial barrier cells in skin, gastrointestinal tract,

and respiratory tract; phagocytes; dendritic cells;

mast cells; natural killer cells; cytokines; and plasma

proteins, including the proteins of the complement

system.

• Epithelia provide physical barriers against microbes;

produce antimicrobial peptides, including defensins

and cathelicidins; and contain lymphocytes that may

prevent infections.

• The principal phagocytes—neutrophils and monocytes/macrophages—are blood cells that are recruited

to sites of infection, where they are activated by

engagement of different receptors. Some activated

macrophages destroy microbes and dead cells, and

other macrophages limit inflammation and initiate

tissue repair.

• Innate lymphoid cells (ILCs) secrete various cytokines that induce inflammation. Natural killer

(NK) cells kill host cells infected by intracellular

microbes and produce the cytokine interferon-?,

which activates macrophages to kill phagocytosed

microbes.

• The complement system is a family of proteins that

are activated on encounter with some microbes (in

innate immunity) and by antibodies (in the humoral

arm of adaptive immunity). Complement proteins

coat (opsonize) microbes for phagocytosis, stimulate

inflammation, and lyse microbes.

• Cytokines of innate immunity function to stimulate

inflammation (TNF, IL-1, IL-6, chemokines), activate NK cells (IL-12), activate macrophages (IFN-?),

and prevent viral infections (type I IFNs).

50 CHAPTER 2 Innate Immunity

• In inflammation, phagocytes are recruited from the

circulation to sites of infection and tissue damage.

The cells bind to endothelial adhesion molecules

that are induced by the cytokines TNF and IL-1 and

migrate in response to soluble chemoattractants,

including chemokines, complement fragments, and

bacterial peptides. The leukocytes are activated, and

they ingest and destroy microbes and damaged cells.

• Antiviral defense is mediated by type I interferons,

which inhibit viral replication, and by NK cells,

which kill infected cells.

• In addition to providing early defense against infections, innate immune responses provide signals

that work together with antigens to activate B and

T lymphocytes. The requirement for these second

signals ensures that adaptive immunity is elicited by

microbes (the most potent inducers of innate immune

reactions) and not by nonmicrobial substances.

REVIEW QUESTIONS

1. How does the specificity of innate immunity differ

from that of adaptive immunity?

2. What are examples of microbial substances recognized by the innate immune system, and what are the

receptors for these substances?

3. What is the inflammasome, and how is it stimulated?

4. What are the mechanisms by which the epithelium of

the skin prevents the entry of microbes?

5. How do phagocytes ingest and kill microbes?

6. What is the role of MHC molecules in the recognition of infected cells by NK cells, and what is the

physiologic significance of this recognition?

7. What are the roles of the cytokines TNF, IL-12, and

type I interferons in defense against infections?

8. How do innate immune responses enhance adaptive

immunity?

Answers to and discussion of the Review Questions are

available at Student Consult.

What Lymphocytes See

Adaptive immune responses are initiated by the recognition of antigens by antigen receptors of lymphocytes.

B and T lymphocytes differ in the types of antigens they

recognize. The antigen receptors of B lymphocytes—

namely, membrane-bound antibodies—can recognize

a variety of macromolecules (proteins, polysaccharides,

lipids, nucleic acids), in soluble form or cell surface–

associated form, as well as small chemicals. Therefore,

B cell–mediated humoral immune responses may be

generated against many types of microbial cell wall and

soluble antigens. The antigen receptors of most T lymphocytes, on the other hand, can see only peptide fragments of protein antigens, and only when these peptides

are displayed on host cell surfaces bound to specialized proteins called major histocompatibility complex

(MHC) molecules. Because the association of antigenic

peptides and MHC molecules occurs inside cells, T cell–

mediated immune responses may be generated only

against protein antigens that are either produced in or

taken up by host cells. This chapter focuses on the nature

of the antigens that are recognized by lymphocytes.

Chapter 4 describes the receptors used by lymphocytes

to detect these antigens.

The induction of immune responses by antigens is a

highly orchestrated process with a number of remarkable features. The first is that very few naive lymphocytes

Antigen Capture and

Presentation to Lymphocytes

CHAPTER OUTLINE

Antigens Recognized by T Lymphocytes, 52

Capture of Protein Antigens by Antigen-Presenting

Cells, 53

Structure and Function of Major Histocompatibility

Complex Molecules, 57

Structure of MHC Molecules, 58

Class I MHC Molecules, 58

Class II MHC Molecules, 58

Properties of MHC Genes and Proteins, 59

Inheritance Patterns and Nomenclature of HLA

Genes, 60

Peptide Binding to MHC Molecules, 61

Processing and Presentation of Protein Antigens, 63

Processing of Cytosolic Antigens for Display by

Class I MHC Molecules, 64

Proteolysis of Cytosolic Proteins, 64

Binding of Peptides to Class I MHC Molecules, 65

Transport of Peptide-MHC Complexes to the Cell

Surface, 65

Processing of Internalized Antigens for Display by

Class II MHC Molecules, 66

Internalization and Proteolysis of Antigens, 66

Binding of Peptides to Class II MHC Molecules, 67

Transport of Peptide-MHC Complexes to the Cell

Surface, 68

Cross-Presentation of Internalized Antigens to

CD8+ T Cells, 68

Physiologic Significance of MHC-Associated Antigen Presentation, 69

Functions of Antigen-Presenting Cells in Addition to

Antigen Display, 71

Antigen Recognition by B Cells and Other Lymphocytes, 71

Summary, 72

52 CHAPTER 3 Antigen Capture and Presentation to Lymphocytes

are specific for any one antigen, as few as 1 in 105 or

106 circulating lymphocytes, and this small fraction of

the body’s lymphocytes needs to locate and react rapidly

to the antigen, wherever it is introduced. Second, different types of adaptive immune responses are required

to defend against different types of microbes. In fact,

the immune system has to react in different ways even

to the same microbe at different stages of the microbe’s

life cycle. For example, defense against a microbe (e.g.,

a virus) that has entered the bloodstream depends on

antibodies that bind the microbe, prevent it from infecting host cells, and help to eliminate it. The production

of potent antibodies requires the activation of CD4+

helper T cells. After it has infected host cells, however,

the microbe is safe from antibodies, which cannot enter

the cells. As a result, activation of CD8+ cytotoxic T lymphocytes (CTLs) may be necessary to kill the infected

cells and eliminate the reservoir of infection. Thus, we

are faced with two important questions:

• How do the rare naive lymphocytes specific for any

microbial antigen find that microbe, especially considering that microbes may enter anywhere in the body?

• How do different types of T cells recognize microbes

in different cellular compartments? Specifically,

helper T cells recognize and respond to both extracellular and intracellular microbes that can be internalized into vesicular compartments in host cells,

whereas CTLs kill infected cells that harbor microbial

antigens in the cytosol and nucleus outside vesicular

compartments. As we shall see in this chapter, MHC

molecules play a central role in this segregation of

antigen recognition by T cells.

The answer to both questions is that the immune system

has developed a highly specialized system for capturing and

displaying antigens to lymphocytes. Research by immunologists, cell biologists, and biochemists has led to a sophisticated understanding of how protein antigens are captured,

broken down, and displayed for recognition by T lymphocytes. This is the major topic of discussion in this chapter.

ANTIGENS RECOGNIZED BY T

LYMPHOCYTES

The majority of T lymphocytes recognize peptide antigens that are bound to and displayed by the MHC molecules of antigen-presenting cells (APCs). The MHC is a

genetic locus whose principal protein products function

as the peptide display molecules of the immune system.

CD4+ and CD8+ T cells can see peptides only when these

peptides are displayed by that individual’s MHC molecules.

This property of T cells is called MHC restriction. The

T cell receptor (TCR) recognizes some amino acid residues of the peptide antigen and simultaneously also recognizes residues of the MHC molecule that is displaying

that peptide (Fig. 3.1). Each TCR, and hence each clone of

CD4+ or CD8+ T cells, recognizes one peptide displayed

by one of the many MHC molecules in every individual.

The properties of MHC molecules and the significance of

MHC restriction are described later in this chapter. How

we generate T cells that recognize peptides presented only

by self MHC molecules is described in Chapter 4. Also,

some small populations of T cells recognize lipid and other

nonpeptide antigens either presented by nonpolymorphic

class I MHC–like molecules or without a requirement for a

specialized antigen display system.

The cells that capture microbial antigens and display them for recognition by T lymphocytes are called

antigen-presenting cells (APCs). Naive T lymphocytes

must see protein antigens presented by dendritic cells

to initiate clonal expansion and differentiation of the

T cells into effector and memory cells. Differentiated

effector T cells again need to see antigens, which may

be presented by various kinds of APCs besides dendritic

cells, to activate the effector functions of the T cells in

both humoral and cell-mediated immune responses. We

first describe how APCs capture and present antigens to

trigger immune responses and then examine the role of

MHC molecules in antigen presentation to T cells.

Fig. 3.1 Model showing how a T cell receptor recognizes

a complex of peptide antigen displayed by an MHC molecule. Major histocompatibility complex (MHC) molecules are

expressed on antigen-presenting cells and function to display

peptides derived from protein antigens. Peptides bind to the

MHC molecules by anchor residues, which attach the peptides

to pockets in the MHC molecules. The antigen receptor of

every T cell recognizes some amino acid residues of the peptide and some (polymorphic) residues of the MHC molecule.

CHAPTER 3 Antigen Capture and Presentation to Lymphocytes 53

CAPTURE OF PROTEIN ANTIGENS BY

ANTIGEN-PRESENTING CELLS

Protein antigens of microbes that enter the body

are captured mainly by dendritic cells and concentrated in the peripheral (secondary) lymphoid

organs, where immune responses are initiated

(Fig. 3.2). Microbes usually enter the body through

the skin (by contact), the gastrointestinal tract (by

ingestion), the respiratory tract (by inhalation), and

the genitourinary tract (by sexual contact). Some

microbes may enter the bloodstream. Microbial antigens can also be produced in any infected tissue.

Because of the vast surface area of the epithelial barriers

and the large volume of blood, connective tissues, and

internal organs, it would be impossible for lymphocytes of all possible specificities to efficiently patrol

all these sites searching for foreign invaders; instead,

antigens are taken to the lymphoid organs through

which lymphocytes recirculate.

Dendritic cellassociated antigen

Skin Gastrointestinal tract Respiratory tract

Venule

To circulation

and spleen To lymph node

antigen-presenting cells

med 2

Thursday, October 13, 2022

No comments:

Post a Comment

cmecde 544458

اتصل بنا