med 2

infection. Naive T cells do not express ligands for Eor P-selectin and do not express receptors for chemokines produced at inflammatory sites. Therefore,

naive T cells do not migrate into sites of infection or

tissue injury.

116 CHAPTER 5 T Cell–Mediated Immunity

The homing of effector T cells to an infected tissue

is independent of antigen recognition, but lymphocytes

that recognize antigens are preferentially retained and

activated at the site. The homing of effector T cells to sites

of infection mainly depends on adhesion molecules and

chemokines. Therefore, any effector T cell present in the

blood, regardless of antigen specificity, can enter the site

of any infection. This nonselective migration presumably

maximizes the chances of effector lymphocytes entering

tissues where they may encounter the microbes they recognize. The effector T cells that leave the circulation and

that specifically recognize microbial antigen presented by

local tissue APCs become reactivated and contribute to

the killing of the microbe in the APC. One consequence

of this reactivation is an increase in the expression of VLA

integrins on the T cells. Some of these integrins specifically

bind to molecules present in the extracellular matrix, such

as hyaluronic acid and fibronectin. Therefore, the antigen-stimulated lymphocytes adhere firmly to the tissue

matrix proteins near the antigen, which may serve to keep

the cells at the inflammatory sites. This selective retention

contributes to accumulation of more and more T cells specific for microbial antigens in the region of the infection.

As a result of this sequence of T cell migration events,

the effector phase of T cell–mediated immune responses

may occur at any site of infection. Whereas the activation of naive T cells requires antigen presentation and

costimulation by dendritic cells, differentiated effector

cells are less dependent on costimulation. Therefore, the

proliferation and differentiation of naive T cells are confined to lymphoid organs, where dendritic cells (which

express abundant costimulators) display antigens, but

the functions of effector T cells may be reactivated by

any host cell displaying microbial peptides bound to

MHC molecules, not just dendritic cells.

Elucidation of the molecular interactions involved

in leukocyte migration has spurred many attempts to

develop agents to block the process of cell migration into

tissues. Antibodies against integrins are effective in the

inflammatory diseases multiple sclerosis and inflammatory bowel disease. The clinical utility of these drugs is

limited by the increased risk of new infection or reactivation of latent infections, because the immune surveillance

function of the T cells is impaired when their migration

into tissues is blocked. A small-molecule inhibitor of the

S1P pathway is used for treating multiple sclerosis, as

mentioned previously. Small molecules that bind to and

block chemokine receptors have also been developed, and

some have shown efficacy in inflammatory bowel disease.

DECLINE OF THE IMMUNE RESPONSE

Because of the remarkable expansion of antigen-specific

lymphocytes at the peak of an immune response, it is predictable that once the response is over, the system must

return to its steady state, called homeostasis, so that it is

prepared to respond to the next infectious pathogen (see

Fig. 5.12). During the response, the survival and proliferation of T cells are maintained by antigen, costimulatory

signals from CD28, and cytokines such as IL-2. Once an

infection is cleared and the stimuli for lymphocyte activation disappear, many of the cells that had proliferated in

response to antigen are deprived of these survival signals.

As a result, these cells die by apoptosis (programmed cell

death). The response subsides within 1 or 2 weeks after

the infection is eradicated, and the only sign that a T cell–

mediated immune response had occurred is the pool of

surviving memory lymphocytes.

To summarize, numerous mechanisms have evolved

to overcome the challenges that T cells face in the generation of a useful cell-mediated immune response:

• Naive T cells need to find the antigen. This problem is

solved by APCs that capture the antigen and concentrate it in specialized lymphoid organs in the regions

through which naive T cells recirculate.

• The correct type of T lymphocytes (i.e., CD4+ helper

T cells or CD8+ CTLs) must respond to antigens

from the endosomal and cytosolic compartments.

This selectivity is determined by the specificity of

the CD4 and CD8 coreceptors for class II and class

I MHC molecules and by the segregation of extracellular (vesicular) and intracellular (cytosolic) protein

antigens for display by class II and class I MHC molecules, respectively.

• T cells should respond to microbial antigens but not

to harmless proteins. This preference for microbes is

maintained because T cell activation requires costimulators that are induced on APCs by microbes.

• Antigen recognition by a small number of T cells must

lead to a response that is large enough to be effective.

This is accomplished by robust clonal expansion after

stimulation and by several amplification mechanisms

induced by microbes and activated T cells themselves

that enhance the response.

• The response must be optimized to combat different

types of microbes. This is accomplished largely by

the development of specialized subsets of effector T

cells.

CHAPTER 5 T Cell–Mediated Immunity 117

SUMMARY

• T lymphocytes are the mediators of the cell-mediated

arm of the adaptive immune system, which combats

microbes that are ingested by phagocytes and live

within these cells or microbes that infect host cells.

T lymphocytes also mediate defense against some

extracellular microbes, help B lymphocytes to produce antibodies, and destroy cancer cells.

• The responses of T lymphocytes consist of sequential

phases: recognition of cell-associated microbes by

naive T cells, expansion of the antigen-specific clones

by proliferation, and differentiation of some of the

progeny into effector cells and memory cells.

• T cells use their antigen receptors to recognize peptide

antigens displayed by MHC molecules on antigen-presenting cells (APCs), which accounts for the specificity

of the ensuing response, and also recognize polymorphic residues of the MHC molecules, accounting for

the MHC restriction of T cell responses.

• Antigen recognition by the T cell receptor (TCR)

triggers signals that are delivered to the interior of

the cells by molecules associated with the TCR (CD3

and ? chains) and by the coreceptors CD4 and CD8,

which recognize class II and class I MHC molecules,

respectively.

• The binding of T cells to APCs is enhanced by adhesion molecules, notably the integrins, whose affinity

for their ligands is increased by antigen recognition

by the TCR.

• APCs exposed to microbes or to cytokines produced as

part of the innate immune reactions to microbes express

costimulators that bind to receptors on T cells and

deliver necessary second signals for T cell activation.

• The biochemical signals triggered in T cells by antigen recognition and costimulation result in the activation of various transcription factors that stimulate

the expression of genes encoding cytokines, cytokine

receptors, and other molecules involved in T cell

responses.

• The signaling pathways involve protein tyrosine

kinases which phosphorylate proteins that become

docking sites for additional kinases and other signaling molecules. The signaling pathways include

the calcineurin/NFAT, RAS-MAP kinase, and PI-3

kinase/MTOR pathways.

• In response to antigen recognition and costimulation, T cells secrete cytokines that induce proliferation of the antigen-stimulated T cells and mediate the

effector functions of T cells.

• T cells proliferate following activation by antigen

and costimulators, resulting in expansion of the antigen-specific clones. The survival and proliferation of

activated T cells are driven by the growth factor IL-2.

• Some of the T cells differentiate into effector cells that

are responsible for eradicating infections. CD4+ effector cells produce surface molecules, notably CD40L,

and secrete various cytokines that activate other leukocytes to destroy microbes. CD8+ effector cells are

able to kill infected and tumor cells.

• Other activated T cells differentiate into memory

cells, which survive even after the antigen is eliminated and are capable of rapid responses to subsequent encounter with the antigen.

• Naive T cells migrate to peripheral lymphoid organs,

mainly lymph nodes draining sites of microbe entry,

whereas many of the effector T cells generated in lymphoid organs are able to migrate to any site of infection.

• The pathways of migration of naive and effector

T cells are controlled by adhesion molecules and

chemokines. The migration of T cells is independent

of antigen, but cells that recognize microbial antigens

in tissues are retained at these sites.

REVIEW QUESTIONS

1. What are the components of the TCR complex?

Which of these components are responsible for antigen recognition and which for signal transduction?

2. What are some of the molecules in addition to the

TCR that T cells use to initiate their responses to antigens, and what are the functions of these molecules?

3. What is costimulation? What is the physiologic significance of costimulation? What are some of the

ligand-receptor pairs involved in costimulation?

4. Summarize the links among antigen recognition, the

major biochemical signaling pathways in T cells, and

the production of transcription factors.

118 CHAPTER 5 T Cell–Mediated Immunity

5. What is the principal growth factor for T cells?

Why do antigen-specific T cells expand more than

other (bystander) T cells on exposure to an antigen?

6. What are the mechanisms by which CD4+ effector T

cells activate other leukocytes?

7. What are the major properties of memory T lymphocytes?

8. Why do naive T cells migrate preferentially to lymphoid organs and differentiated effector T cells

(which have been activated by antigen) migrate preferentially to tissues that are sites of infection?

Answers to and discussion of the Review Questions are

available at Student Consult.

119

Functions of T Cells in Host Defense

Host defense in which T lymphocytes serve as effector cells is called cell-mediated immunity. T cells are

essential for eliminating microbes that survive and

replicate inside cells and for eradicating infections

by some extracellular microbes, often by recruiting

other leukocytes to clear the infectious pathogens.

T cells also destroy tumors that produce proteins that

are recognized as foreign antigens (see Chapter 10). In

this chapter, we focus on the role of T cell responses in

defense against pathogenic microbes. Cell-mediated

immune responses begin with the activation of naive

T cells to proliferate and to differentiate into effector cells. The majority of these effector T cells then

migrate to sites of infection, where they function to

eliminate the microbes. Some CD4+ effector cells stay

in lymphoid organs and help B lymphocytes to produce high-affinity antibodies (humoral immunity, see

Chapter 7). In Chapter 3 we described the function of

major histocompatibility complex (MHC) molecules

in displaying the antigens of intracellular microbes for

recognition by T lymphocytes, and in Chapter 5 we

discussed the early events in the activation of naive T

lymphocytes. In this chapter, we address the following

questions:

• What types of effector T cells are involved in the

elimination of microbes?

• How do effector T cells develop from naive T cells,

and how do effector cells eradicate infections by

diverse microbes?

• What are the roles of macrophages and other leukocytes in the destruction of infectious pathogens?

TYPES OF T CELL–MEDIATED IMMUNE

REACTIONS

Two main types of cell-mediated immune reactions

eliminate different types of microbes: CD4+ helper

T cells express molecules that recruit and activate

other leukocytes to phagocytose (ingest) and destroy

microbes, and CD8+ cytotoxic T lymphocytes (CTLs)

kill infected cells containing microbial proteins in

the cytosol, thus eliminating cellular reservoirs of

infection (Fig. 6.1). Microbial infections may occur

anywhere in the body, and some infectious pathogens

Effector Mechanisms of

T Cell–Mediated Immunity

CHAPTER OUTLINE

Types of T Cell–Mediated Immune Reactions, 119

Development and Functions of CD4+ Effector T

Lymphocytes, 122

Subsets of CD4+ Helper T Cells Distinguished by

Cytokine Profiles, 122

Th1 Cells, 123

Development of Th1 Cells, 125

Th2 Cells, 125

Development of Th2 Cells, 128

Th17 Cells, 129

Development of Th17 Cells, 130

Differentiation and Functions of CD8+ Cytotoxic T

Lymphocytes, 131

Resistance of Pathogenic Microbes to Cell-Mediated

Immunity, 132

Summary, 136

120 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

are able to infect and live within host cells. Pathogenic

microbes that infect and survive inside host cells include

(1) many bacteria, fungi, and protozoa that are ingested

by phagocytes but resist the killing mechanisms of these

phagocytes and thus survive in vesicles or in the cytosol,

and (2) viruses that infect phagocytic and nonphagocytic cells and replicate in these cells (see Chapter 5,

Fig. 5.1). CD4+ and CD8+ T cells recognize microbes in

different cellular compartments and differ in the nature

of the reactions they elicit. In general, CD4+ T cells recognize antigens of microbes that may be intracellular

or extracellular (based on where the microbes survive

and replicate) but whose antigens are internalized into

endocytic vesicles. These T cells secrete cytokines that

recruit and activate phagocytes and other leukocytes

that kill the microbes. In contrast, CD8+ T cells recognize microbial antigens that are present in the cytosol of

infected cells and destroy these cells.

Cell-mediated immunity against pathogens was discovered as a form of immunity to an intracellular bacterial infection that could be transferred from immune

animals to naive animals by cells (now known to be T

lymphocytes) but not by serum antibodies (Fig. 6.2). It

was known from early studies that lymphocytes were

responsible for the specificity of cell-mediated immunity against different microbes, but the elimination of

the microbes was a function of activated macrophages.

As already mentioned, CD4+ T cells are mainly responsible for this classical type of cell-mediated immunity,

whereas CD8+ T cells can eradicate infections without

a requirement for phagocytes.

T cell–mediated immune reactions consist of multiple steps (see Chapter 5, Fig. 5.2). Naive T cells are

stimulated by microbial antigens in peripheral (secondary) lymphoid organs, giving rise to effector T cells

whose function is to eradicate the infections. The differentiated effector T cells then migrate to the site of

infection. Phagocytes at these sites that have ingested

the microbes or microbial proteins into intracellular

vesicles display peptide fragments of the protein antigens bound to cell surface class II MHC molecules

for recognition by CD4+ effector T cells. Peptide antigens derived from microbial proteins in the cytosol of

infected cells are displayed by class I MHC molecules

for recognition by CD8+ effector T cells. Antigen recognition activates the effector T cells to perform their

Infected cell with

microbial antigens in

cytoplasm

Killing of

infected cells

Phagocyte with ingested microbes

Macrophage activation

Fig. 6.1 Cell-mediated Immunity. A, Effector T cells of the CD4+ Th1 and Th17 subsets recognize microbial antigens and secrete cytokines that recruit leukocytes (inflammation) and activate phagocytes to kill the

microbes. Effector cells of the Th2 subset (not shown) recruit eosinophils, which destroy helminthic parasites. B, CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells with microbial antigens in the cytosol. CD8+

T cells also produce cytokines that induce inflammation and activate macrophages (not shown).

CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity 121

1 2 3 4

Number of viable Listeria

A T lymphocytes adoptively

transfer specific immunity

Number of viable Listeria

transfer specific immunity

% Killing of Listeria in vitro

Leukocytes added (x10-6)

100

Only activated macrophages

kill Listeria in vitro

1.0 2.0 3.0 4.0 5.0 6.0

Immune T cells

Resting macrophages

Activated macrophages

Fig. 6.2 Cell-mediated immunity to an intracellular bacterium, Listeria monocytogenes. In these experiments, a sample of lymphocytes or serum (a source of antibodies) was taken from a mouse that had previously been exposed to a sublethal dose of Listeria organisms (immune mouse) and transferred to a normal

(naive) mouse, and the recipient of the adoptive transfer was challenged with the bacteria. The number of

bacteria were measured in the spleen of the recipient mouse to determine if the transfer had conferred

immunity. Protection against bacterial challenge (seen by reduced recovery of live bacteria) was induced by

the transfer of immune lymphoid cells, now known to be T cells (A), but not by the transfer of serum (B). The

bacteria were killed in vitro by activated macrophages but not by T cells (C). Therefore protection depends on

antigen-specific T lymphocytes, but bacterial killing is the function of activated macrophages.

122 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

task of eliminating the infectious pathogens. Thus, in

cell-mediated immunity, T cells recognize protein antigens at two stages. First, naive T cells recognize antigens in lymphoid tissues and respond by proliferating

and by differentiating into effector cells (see Chapter

5). Second, effector T cells recognize the same antigens anywhere in the body and respond by eliminating

these microbes.

This chapter describes how CD4+ and CD8+ effector

T cells develop in response to microbes and eliminate

these microbes. Because CD4+ helper T lymphocytes

and CD8+ CTLs use distinct mechanisms to combat

infections, we discuss the development and functions of

the effector cells of these lymphocyte classes individually. We conclude by describing how the two classes of

lymphocytes may cooperate to eliminate intracellular

microbes.

DEVELOPMENT AND FUNCTIONS OF CD4+

EFFECTOR T LYMPHOCYTES

In Chapter 5 we introduced the concept that effector

cells of the CD4+ lineage could be distinguished on the

basis of the cytokines they produce. These subsets of

CD4+ T cells differ in their functions and serve distinct

roles in cell-mediated immunity.

Subsets of CD4+ Helper T Cells Distinguished

by Cytokine Profiles

Analysis of cytokine production by helper T (Th) cells

has revealed that functionally distinct subsets of CD4+

T cells exist that produce different cytokines and that

eliminate different types of pathogens. The existence

of these subsets illustrates how the immune system

mounts specialized responses that are optimized to

combat diverse microbes. For example, intracellular microbes such as mycobacteria are ingested by

phagocytes but resist intracellular killing. The adaptive immune response to such microbes results in the

activation of the phagocytes, enabling them to kill the

ingested microbes. In contrast, the immune response

to helminths is dominated by the production of immunoglobulin E (IgE) antibodies and the activation of

eosinophils, which destroy the helminths. The immune

response to extracellular bacteria and fungi requires

cytokines that help to drive neutrophilic inflammation,

because neutrophils in large numbers are needed to

eliminate these pathogens. All these types of immune

responses depend on CD4+ helper T cells, but for many

years it was not clear how the CD4+ helper cells are

able to stimulate such distinct immune effector mechanisms. We now know that these responses are mediated

by subpopulations of CD4+ effector T cells that produce

different cytokines.

CD4+ helper T cells may differentiate into three

subsets of effector cells that produce distinct sets of

cytokines that function to defend against different

types of microbial infections in tissues, and a fourth

subset that activates B cells in secondary lymphoid

organs (Fig. 6.3). The subsets that were defined first

are called Th1 cells and Th2 cells (for type 1 helper T

cells and type 2 helper T cells, respectively); the third

population, which was identified later, is called Th17

cells because its signature cytokine is interleukin (IL)-

17. The T cells that help B lymphocytes, called follicular

helper T (Tfh) cells, are described in Chapter 7 and will

not be considered further in this chapter. The discovery

of these subpopulations has been an important milestone in understanding immune responses and provides

models for studying the process of cell differentiation.

However, it should be noted that some activated CD4+

T cells may produce mixtures of cytokines and therefore cannot be readily classified into these subsets, and

there may be plasticity in these populations so that one

subset may convert into another under some conditions. Despite these caveats, considering the functions

of CD4+ effector cells in the context of the major subsets

is helpful for understanding the mechanisms of cellmediated immunity.

The cytokines produced in adaptive immune

responses include those made by the Th subsets, as

well as cytokines produced by CD4+ regulatory T cells

and CD8+ T cells. These cytokines of adaptive immunity share some general properties, but they each have

different biologic activities and play unique roles in

the effector phase or regulation of these responses

(Fig. 6.4). The functions of the CD4+ T cell subsets

reflect the actions of the cytokines they produce. Similar

sets of cytokines may be produced early in immune

responses by innate lymphoid cells, such as ILC1,

ILC2, and ILC3 (see Chapter 2), and later by Th1, Th2,

and Th17 cells, respectively. These combined innate

and adaptive responses with similar cytokine profiles and functional outcomes are sometimes grouped

under “type 1 immunity,” “type 2 immunity,” and “type

3 immunity.”

CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity 123

Each subset of CD4+ T cells develops in response

to the types of microbes that subset is best at eradicating. Different microbes elicit the production of different

cytokines from dendritic cells and other cells, and these

cytokines drive the differentiation of antigen-activated

T cells to one or another subset. We next discuss the

functions and development of each of the major subsets

of CD4+ effector T cells.

Th1 Cells

The Th1 subset is induced by microbes that are

ingested by and activate phagocytes, primarily macrophages, and Th1 cells stimulate phagocyte-mediated

killing of ingested microbes (Fig. 6.5). The signature cytokine of Th1 cells is interferon-? (IFN-?), the

most potent macrophage-activating cytokine known.

(Despite its similar name, IFN-? is a much less potent

antiviral cytokine than the type I IFNs [see Chapter 2]).

Th1 cells, acting through CD40 ligand and IFN-?,

increase the ability of macrophages to kill phagocytosed microbes (Fig. 6.6). Macrophages ingest and

attempt to destroy microbes as part of the innate immune

response (see Chapter 2). The efficiency of this process

is greatly enhanced by the interaction of Th1 cells with

the macrophages. When microbes are ingested into phagosomes of the macrophages, microbial peptides are presented on class II MHC molecules and are recognized by

CD4+ T cells. If these T cells belong to the Th1 subset,

they are induced to express CD40 ligand (CD40L, or

CD154) and to secrete IFN-?. Binding of CD40L to CD40

on macrophages functions together with IFN-? binding

to its receptor on the same macrophages to trigger biochemical signaling pathways that lead to the generation

of reactive oxygen species (ROS) and nitric oxide (NO)

and activation of lysosomal proteases. All these molecules

are potent destroyers of microbes. The net result of CD40-

mediated and IFN-?–mediated activation is that macrophages become strongly microbicidal and can destroy

most ingested microbes. This pathway of macrophage

activation by CD40L and IFN-? is called classical macrophage activation, in contrast to Th2-mediated alternative macrophage activation, discussed later. Classically

mast cell activation;

Fig. 6.3 Characteristics of subsets of CD4+ helper T lymphocytes. A naive CD4+ T cell may differentiate

into subsets that produce different cytokines that recruit and activate different cell types (referred to as target

cells) and combat different types of infections in host defense. These subsets also are involved in various

kinds of inflammatory diseases. The table summarizes the major differences among Th1, Th2, Th17, and Tfh

subsets of helper T cells. IFN, Interferon; IL, interleukin.

124 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

Biologic actions of selected T cell cytokines

Cytokine Principal action Cellular source(s)

innate lymphoid cells

CD4+ Th2 T cells,

mast cells,

innate lymphoid cells

Activation of

eosinophils

B cell switching to IgE;

alternative macrophage

activation

B cell switching to IgE;

alternative macrophage

activation

CD4+ Th1 and

CD8+ T cells,

natural killer (NK) cells

Activation of

macrophages

(classical pathway)

General properties of T cell cytokines

Property Significance

Produced transiently in response

to antigen

Provides diversity of actions but

may limit clinical utility of cytokines

because of unwanted effects

Systemic effects of cytokines

usually reflect severe infections

or autoimmunity

Provides cytokine only when

needed

Usually acts on same cell that

produces the cytokine (autocrine)

or nearby cells (paracrine)

Pleiotropism: each cytokine has

multiple biological actions

Blocking any one cytokine may

not achieve a desired effect

Redundancy: multiple cytokines

may share the same or similar

biological activities

IL-4

IL-5

IL-13

T cell proliferation; Activated T cells

regulatory T cell survival

B cell activation; CD4+ Tfh T cells

innate lymphoid cells

Maintenance of

epithelial barrier function

IL-22

Interferon-?

(IFN-?)

Fig. 6.4 Properties of the major cytokines produced by CD4+ helper T lymphocytes. A, General properties of cytokines produced during adaptive immune responses. B, Functions of cytokines involved in T

cell–mediated immunity. Note that IL-2, which is produced by T cells early after activation and is the first

identified T cell cytokine, was discussed in Chapter 5 in the context of T cell activation. Transforming growth

factor ß (TGF-ß) functions mainly as an inhibitor of immune responses; its role is discussed in Chapter 9. The

cytokines of innate immunity are shown in Fig. 2.14; several of these are also made by T cells and thus function in adaptive immunity as well. More information about these cytokines and their receptors is provided in

Appendix III. IgE, Immunoglobulin E; IL, interleukin.

CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity 125

activated macrophages, often called M1 macrophages,

also secrete cytokines that stimulate inflammation and

express increased levels of MHC molecules and costimulators, which amplify the T cell response. CD8+ T cells

secrete IFN-? as well, and may contribute to macrophage

activation and killing of ingested microbes.

The critical role of Th1 cells in defense against intracellular microbes is demonstrated by the fact that individuals with inherited defects in the development or

function of this subset are susceptible to infections with

such microbes, especially prevalent nontuberculous

mycobacterial species that do not infect immunocompetent individuals.

Essentially the same reaction, consisting of leukocyte

recruitment and activation, may be elicited by injecting a

microbial (or other) protein into the skin of an individual

who has been immunized with the protein or previously

infected with the microbe. This reaction is called delayedtype hypersensitivity (DTH), and it is described in

Chapter 11 when we discuss injurious immune reactions.

Development of Th1 Cells

The differentiation of naive CD4+ T cells to Th1 effector

cells is driven by a combination of antigen-induced T

cell receptor (TCR) signaling and the cytokines IL-12

and IFN-? (Fig. 6.7A). In response to many bacteria

(especially intracellular bacteria) and viruses, dendritic

cells and macrophages produce IL-12, and natural

killer (NK) cells produce IFN-?. Therefore, when naive

T cells recognize the antigens of these microbes, the T

cells are also exposed to IL-12 and IFN-?. Type I IFNs,

produced in response to viral infections, also promote

Th1 differentiation. IL-12 and IFN-? activate the transcription factors Stat4 and Stat1, respectively, and antigen-induced signals in combination with the cytokines

induce expression of a transcription factor called T-bet

that is essential for Th1 development and function.

These transcription factors work together to stimulate

the expression of IFN-? and other proteins involved in

the migration of Th1 cells to sites of infection. Note that

IFN-? not only activates macrophages to kill ingested

microbes but also promotes more Th1 development

and inhibits the development of Th2 and Th17 cells.

Thus, IFN-? increasingly polarizes the response to the

Th1 subset.

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