The outcome of infections is influenced by the

strength of host defenses and the ability of pathogens

to resist these defenses. The same principle is evident

when the effector mechanisms of humoral immunity

are considered. One approach for tilting the balance

between the host and microbes in favor of protective immunity is to vaccinate individuals to enhance

adaptive immune responses. The principles underlying

vaccination strategies are described at the end of Chapter 8, after the discussion of humoral immunity.

As we will discuss in Chapter 10, tumors, like infectious pathogens, have developed several mechanisms for

evading or resisting CD8+ T cell–mediated immunity.

These mechanisms include inhibiting expression of class

I MHC molecules and inducing T cell exhaustion. Blocking some of these evasion mechanisms provides effective strategies for unleashing antitumor immunity (see

Chapter 10).

Viral

load

Memory T cells:

Protective

response

to virus

T cell response

T cell response

Effector

T cells

Time

Viral load

Exhausted

T cells:

Inability to

respond to

virus

PD-1

CTLA-4

Effector

T cells

Time

A Acute infection

B Chronic infection

Fig. 6.15 T cell activation and exhaustion. A, In an acute viral infection, virus-specific CD8+ T cells proliferate, differentiate into effector CTLs and memory cells, and clear the virus. B, In some chronic viral infections,

CD8+ T cells mount an initial response but begin to express inhibitory receptors (such as PD-1 and CTLA-4)

and are inactivated, leading to persistence of the virus. This process is called exhaustion because the T cells

do make a response, but this is short lived.

136 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

SUMMARY

• Cell-mediated immunity is the arm of adaptive

immunity that eradicates infections by cell-associated

microbes. This form of host defense uses two types of

T cells: CD4+ helper T cells recruit and activate phagocytes to kill ingested and some extracellular microbes,

and CD8+ CTLs eliminate the reservoirs of infection

by killing cells harboring microbes in the cytosol.

• CD4+ T cells can differentiate into subsets of effector

cells that make different cytokines and perform distinct functions.

• Effector cells of the Th1 subset recognize the antigens

of microbes that have been ingested by macrophages.

These T cells secrete IFN-? and express CD40 ligand,

which function cooperatively to activate macrophages.

• Classically activated macrophages produce substances, including ROS, NO, and lysosomal enzymes,

that kill ingested microbes. Macrophages also produce cytokines that induce inflammation.

• Th2 cells stimulate eosinophilic inflammation and

trigger the alternative pathway of macrophage activation, and Tfh cells induced in parallel trigger IgE

production. IgE and eosinophils are important in

host defense against helminthic parasites.

• The balance between activation of Th1 and Th2

cells determines the outcomes of many infections,

with Th1 cells promoting and Th2 cells suppressing

defense against intracellular microbes.

• Th17 cells enhance neutrophil and monocyte recruitment and acute inflammation, which is essential for

defense against certain extracellular bacteria and

fungi.

• CD8+ T cells differentiate into CTLs that kill infected

cells, mainly by inducing apoptosis of the infected

cells. CD4+ and CD8+ T cells often function cooperatively to eradicate intracellular infections. CD8+

CTLs also kill cancer cells and are the key mediators

of antitumor immunity.

• Many pathogenic microbes have evolved mechanisms to resist cell-mediated immunity. These mechanisms include inhibiting phagolysosome fusion,

escaping from the vesicles of phagocytes, inhibiting

the assembly of class I MHC–peptide complexes,

producing inhibitory cytokines or decoy cytokine

receptors, and inactivating T cells, thus prematurely

terminating T cell responses.

REVIEW QUESTIONS

1. What are the types of T lymphocyte–mediated

immune reactions that eliminate microbes that are

sequestered in the vesicles of phagocytes and microbes

that live in the cytoplasm of infected host cells?

2. What are the major subsets of CD4+ effector T cells,

how do they differ, and what are their roles in defense

against different types of infectious pathogens?

3. What are the mechanisms by which T cells activate

macrophages, and what are the responses of macrophages that result in the killing of ingested microbes?

4. How do CD8+ CTLs kill cells infected with viruses?

5. What are some of the mechanisms by which intracellular microbes resist the effector mechanisms of

cell-mediated immunity?

Answers to and discussion of the Review Questions are

available at Student Consult.

137

Activation of B Lymphocytes

and Production of Antibodies

7

Humoral immunity is mediated by antibodies and is the

arm of the adaptive immune response that functions

to neutralize and eliminate extracellular microbes and

microbial toxins. Humoral immunity is the principal

defense mechanism against microbes with capsules rich

in polysaccharides and lipids, because antibodies can be

produced against polysaccharides and lipids but T cells

cannot respond to nonprotein antigens. Antibodies are

produced by B lymphocytes and their progeny. Naive B

lymphocytes recognize antigens but do not secrete antibodies, and activation of these cells stimulates their differentiation into antibody-secreting plasma cells.

This chapter describes the process and mechanisms

of B cell activation and antibody production, focusing

on the following questions:

• How are antigen receptor–expressing naive B lymphocytes activated and converted to antibody secreting cells?

• How is the process of B cell activation regulated so

that the most useful types of antibodies are produced

in response to different types of microbes?

Chapter 8 describes how the antibodies that are produced during humoral immune responses function to

defend individuals against microbes and toxins.

PHASES AND TYPES OF HUMORAL

IMMUNE RESPONSES

The activation of B lymphocytes results in their proliferation, leading to expansion of antigen-specific

clones, and their differentiation into plasma cells,

which secrete antibodies (Fig. 7.1). Naive B lymphocytes express two classes of membrane-bound antibodies, immunoglobulins M and D (IgM and IgD),

that function as receptors for antigens. These naive B

cells are activated by antigen binding to membrane

Humoral Immune Responses

CHAPTER OUTLINE

Phases and Types of Humoral Immune Responses, 137

Stimulation of B Lymphocytes by Antigen, 141

Antigen-Induced Signaling in B Cells, 141

Role of Innate Immune Signals in B Cell Activation, 141

Functional Consequences of B Cell Activation by

Antigen, 143

Functions of Helper T Lymphocytes in Humoral

Immune Responses, 145

Activation and Migration of Helper T Cells and B

Cells, 145

Presentation of Antigens by B Lymphocytes to

Helper T Cells, 146

Mechanisms of Helper T Cell–Mediated Activation

of B Lymphocytes, 147

Extrafollicular and Germinal Center Reactions, 147

Heavy-Chain Isotype (Class) Switching, 149

Affinity Maturation, 152

Generation of Plasma Cells and Memory B Cells, 154

Antibody Responses to T-Independent Antigens, 154

Regulation of Humoral Immune Responses:

Antibody Feedback, 155

Summary, 156

138 CHAPTER 7 Humoral Immune Responses

immunoglobulin (Ig) and by other signals discussed

later in the chapter. The antibodies secreted in response

to an antigen have the same specificity as the surface

receptors on naive B cells that recognize that antigen in

order to initiate the response. One activated B cell may

generate a few thousand plasma cells, each of which

can produce copious amounts of antibody, in the range

of several thousand molecules per hour. In this way,

humoral immunity can keep pace with rapidly proliferating microbes. During their differentiation, some

B cells may begin to produce antibodies of different

heavy-chain isotypes (or classes) that mediate different

effector functions and are specialized to combat different types of microbes. This process is called heavychain isotype (or class) switching. During the course of

a B cell response to an infection, the affinity of antibodies specific for microbial proteins increases over time.

This process is called affinity maturation, and it leads to

the production of antibodies with improved capacity to

bind to and neutralize microbes and their toxins.

Antibody responses to different antigens are classified as T-dependent or T-independent, based on the

requirement for T cell help (Fig. 7.2). B lymphocytes recognize and are activated by a wide variety of chemically

distinct antigens, including proteins, polysaccharides, lipids, nucleic acids, and small chemicals. Helper T lymphocytes play an important role in B cell activation by protein

antigens. (The designation helper came from the discovery that some T cells stimulate, or help, B lymphocytes to

produce antibodies.) T cells help B cells respond to only

protein antigens because T cells can only recognize peptides derived from proteins presented as peptide–major

histocompatibility complex (MHC) complexes. In the

absence of T cell help, most protein antigens elicit weak

or no antibody responses. Therefore, protein antigens and

the antibody responses to these antigens are called T-dependent. Polysaccharides, nucleic acids, lipids, and other

multivalent antigens (which contain the same structural

unit repeated multiple times in tandem) can stimulate

antibody production without the involvement of helper

T cells. Therefore, these multivalent nonprotein antigens

and the antibody responses to them are called T-independent. The antibodies produced in response to proteins

exhibit more isotype switching and affinity maturation

Antibody

secretion

Isotype

switching

Affinity

maturation

Memory

B cell

IgM

Highaffinity IgG

Activated

B cell

Naive

IgM+, IgD+

B cell

Helper T cells,

other stimuli

Microbe

IgG-expressing

B cell

Antibody-secreting

plasma cells

IgG

Outcome

Activation of

B lymphocytes

Antigen Differentiation

recognition

High-affinity

Ig-expressing

B cell

Proliferation

Fig. 7.1 Phases of humoral immune responses. Naive B lymphocytes recognize antigens, and under the

influence of helper T cells and other stimuli (not shown), the B cells are activated to proliferate, giving rise

to clonal expansion, and to differentiate into antibody-secreting plasma cells. Some of the activated B cells

undergo heavy-chain isotype switching and affinity maturation, and some become long-lived memory cells.

CHAPTER 7 Humoral Immune Responses 139

than antibodies against T-independent antigens because

helper T cells stimulate these processes. Furthermore,

T-dependent antigens stimulate the generation of longlived plasma cells and memory B cells. Thus, the most

specialized and long-lived antibody responses involve

protein antigens and are generated under the influence

of helper T cells, whereas T-independent responses are

relatively simple and transient, and involve only the direct

activation of B cells by antigens.

Different subsets of B cells respond preferentially

to T-dependent and T-independent antigens (see Fig.

7.2). The majority of B cells are called follicular B cells

because they reside in and circulate through the follicles

of lymphoid organs (see Chapter 1). These follicular B cells

make the bulk of T-dependent, class-switched, and highaffinity antibody responses to protein antigens and give

rise to long-lived plasma cells. Marginal-zone B cells,

which are located in the peripheral region of the splenic

white pulp and also in the outer rim of follicles in lymph

nodes, respond largely to blood-borne polysaccharide and

lipid antigens; B-1 cells respond to multivalent antigens in

the mucosal tissues and peritoneum. Marginal-zone B cells

and B-1 cells express antigen receptors of limited diversity

and make predominantly T-independent IgM responses.

IgM antibodies may be produced spontaneously by B-1

cells, without overt immunization. These antibodies, called

natural antibodies, may help to clear some cells that die

by apoptosis during normal cell turnover and may also

provide protection against some bacterial pathogens.

Antibody responses generated during the first exposure to an antigen, called primary responses, differ quantitatively and qualitatively from responses to subsequent

exposures, called secondary responses (Fig. 7.3). The

amounts of antibody produced in the primary immune

response are smaller than the amounts produced in secondary responses. In secondary responses to protein antigens, there is increased heavy-chain isotype switching and

affinity maturation, because repeated stimulation by a protein antigen leads to an increase in the number and activity

of helper T lymphocytes.

T-dependent

IgM

Follicular

B cells

IgM

Protein

antigen

Helper

T cell

Isotype-switched,

high-affinity antibodies;

memory B cells,

long-lived plasma cells

IgG

IgA

IgE