mainly as a result of delivery of granule proteins into

the target cells. Two types of granule proteins critical for

Extracellular

fungi,

bacteria

Inflammation,

neutrophil response

Anti-microbial

peptides

Increased

barrier

integrity

Leukocytes

and tissue cells Epithelial

cells

Th17 cells

IL-17 IL-22

Chemokines, TNF,

IL-1, IL-6, CSFs

Naive CD4+

T cell

Proliferation and

differentiation

APC

Fig. 6.11 Functions of Th17 cells. Th17 cells produce the

cytokine interleukin-17 (IL-17), which induces production of

chemokines and other cytokines from various cells, and these

recruit neutrophils (and monocytes, not shown) into the site of

inflammation. Some of the cytokines made by Th17 cells, notably IL-22, function to maintain epithelial barrier function in the

intestinal tract and other tissues. APC, Antigen-presenting cell;

CSFs, colony-stimulating factors; TNF, tumor necrosis factor.

132 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

killing are granzymes (granule enzymes) and perforin.

Perforin disrupts the integrity of the target cell plasma

membrane and endosomal membranes, thereby facilitating the delivery of granzymes into the cytosol. Granzymes (granule enzymes) cleave and thereby activate

enzymes called caspases (cysteine proteases that cleave

proteins after aspartic acid residues) that are present in

the cytosol of target cells and whose major function is to

induce apoptosis.

Activated CTLs also express a membrane protein

called Fas ligand, which binds to a death-inducing receptor, called Fas (CD95), on target cells. Engagement of Fas

activates caspases and induces target cell apoptosis; this

pathway does not require granule exocytosis and probably plays only a minor role in killing by CD8+ CTLs.

The net result of these effector mechanisms of CTLs

is that the infected cells are killed. Cells that have undergone apoptosis are rapidly phagocytosed and eliminated.

CTLs themselves are not injured during the process

of killing other cells, so each CTL can kill a target cell,

detach, and go on to kill additional targets.

In addition to their cytotoxic activity, CD8+ effector cells secrete IFN-?. This cytokine is responsible for

activation of macrophages in infections and in disease

states where excessive activation of CD8+ T cells may

be a feature. It may also play a role in defense against

some tumors.

Although we have described the effector functions of

CD4+ T cells and CD8+ T cells separately, these types

of T lymphocytes may function cooperatively to destroy

intracellular microbes (Fig. 6.13). If microbes are

phagocytosed and remain sequestered in macrophage

vesicles, CD4+ T cells may be adequate to eradicate these

infections by secreting IFN-? and activating the microbicidal mechanisms of the macrophages. However, if the

microbes are able to escape from vesicles into the cytoplasm, they become insusceptible to the killing mechanisms of activated macrophages, and their elimination

requires destruction of the infected cells by CD8+ CTLs.

RESISTANCE OF PATHOGENIC MICROBES

TO CELL-MEDIATED IMMUNITY

Different microbes have developed diverse mechanisms to resist T lymphocyte–mediated host

defense (Fig. 6.14). Many intracellular bacteria,

CTL activation

and granule

exocytosis

LFA-1 CD8

ICAM-1

Granzymes

Perforin

Apoptosis

of target cell

Target

cell

CD8+

CTL

Perforin facilitates

entry of

granzymes into

the cytosol,

granzymes

activate apoptosis

Antigen recognition

and binding of

CTL to target cell

Fig. 6.12 Mechanisms of killing of infected cells by CD8+ cytotoxic T lymphocytes (CTLs). CTLs recognize class I major histocompatibility complex (MHC)–associated peptides of cytoplasmic microbes in infected

cells and form tight adhesions (conjugates) with these cells. Adhesion molecules such as integrins stabilize

the binding of the CTLs to infected cells (not shown). The CTLs are activated to release (exocytose) their

granule contents (perforin and granzymes) toward the infected cell, referred to as the target cell. Granzymes

are delivered to the cytosol of the target cell by a perforin-dependent mechanism. Granzymes then induce

apoptosis. ICAM-1, Intercellular adhesion molecule 1; LFA-1, leukocyte function–associated antigen 1.

CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity 133

such as Mycobacterium tuberculosis, Legionella

pneumophila, and Listeria monocytogenes, inhibit

the fusion of phagosomes with lysosomes or create pores in phagosome membranes, allowing these

organisms to escape into the cytosol. Thus, these

microbes are able to resist the microbicidal mechanisms of phagocytes and survive and even replicate inside phagocytes. Many viruses inhibit class I

MHC–associated antigen presentation by inhibiting

production or expression of class I molecules, by

blocking transport of antigenic peptides from the

cytosol into the endoplasmic reticulum (ER) and by

removing newly synthesized class I molecules from

the ER. All these viral mechanisms reduce the loading of class I MHC molecules by viral peptides. The

result of this defective loading is reduced surface

expression of class I MHC molecules, because empty

class I molecules are unstable and are not expressed

on the cell surface. It is interesting that NK cells

are activated by class I–deficient cells (see Chapter 2). Thus, host defenses have evolved to combat

immune evasion mechanisms of microbes: CTLs

recognize class I MHC–associated viral peptides,

viruses inhibit class I MHC expression, and NK cells

recognize the absence of class I MHC molecules on

infected or stressed cells.

Other viruses produce inhibitory cytokines or soluble (decoy) cytokine receptors that bind and neutralize cytokines such as IFN-?, reducing the amount of

cytokines available to trigger cell-mediated immune

reactions. Some viruses evade elimination and establish chronic infections by stimulating expression of

inhibitory receptors, including PD-1 (programmed

[cell] death protein 1; see Chapter 9) on CD8+ T cells,

thus inhibiting the effector functions of CTLs. This

phenomenon, in which the T cells mount an initial

response against the virus but the response is prematurely terminated, has been called T cell exhaustion (Fig. 6.15). It typically occurs as a reaction to

chronic antigenic stimulation, as in chronic viral

infections or tumors, and is a mechanism by which

the repeatedly stimulated T cell terminates its own

CD4+

T cell

CD8+

CTL

Killing of

microbes in

phagolysosomes

Killing

of infected

cell

Phagocytosed microbes

in vesicles and cytosol

Viable

microbe in

cytosol

IFN-?

Fig. 6.13 Cooperation between CD4+ and CD8+ T cells in eradication of intracellular infections. In a

macrophage infected by an intracellular bacterium, some of the bacteria are sequestered in vesicles (phagosomes), and others may escape into the cytosol. CD4+ T cells recognize antigens derived from the vesicular

microbes and activate the macrophage to kill the microbes in the vesicles. CD8+ T cells recognize antigens

derived from the cytosolic bacteria and are needed to kill the infected cell, thus eliminating the reservoir of

infection. CTL, Cytotoxic T lymphocyte; IFN, interferon.

134 CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity

Microbe Mechanism

Mycobacteria

Herpes simplex

virus (HSV)

Cytomegalovirus

(CMV)

Epstein-Barr

virus (EBV)

Pox virus

Inhibition of

phagolysosome fusion

Inhibition of antigen

presentation: HSV

peptide interferes with

TAP transporter

Inhibition of antigen

presentation: inhibition

of proteasomal activity;

removal of class I

MHC molecules from

endoplasmic

reticulum (ER)

Inhibition of antigen

presentation: inhibition

of proteasomal activity

Inhibition of effector

cell activation:

production of soluble

cytokine receptors

Epstein-Barr

virus (EBV)

Production of IL-10,

inhibition of

macrophage and

dendritic cell activation

Mycobacteria

survive within

phagosome

Inhibition

of antigen

presentation

Lysosome

with

enzymes

Phagosome

with ingested

mycobacteria

EBV infected

B lymphocyte

EBV IL-10

Macrophage

Inhibition of

macrophage

activation

IL-1,

IFN-?

Pox virus

Block cytokine

activation of

effector cells

Soluble

IL-1 or IFN-?

receptors

ER

Cytosolic protein

Proteasome

TAP

CD8+

CTL

HSV

EBV, CMV

CMV

Fig. 6.14 Evasion of cell-mediated immunity (CMI) by microbes. Select examples of different mechanisms by which bacteria and viruses resist the effector mechanisms of CMI. CTL, Cytotoxic T lymphocyte; ER,

endoplasmic reticulum; IFN, interferon; IL, interleukin; TAP, transporter associated with antigen processing.

CHAPTER 6 Effector Mechanisms of T Cell–Mediated Immunity 135

response. Still other viruses directly infect and kill

immune cells, the best example being human immunodeficiency virus (HIV), which is able to survive in

infected persons by killing CD4+ T cells.