One of the remarkable properties of the normal immune
system is that it can react to an enormous variety of
microbes but does not react against the individual’s own
(self) antigens. This unresponsiveness to self antigens,
also called immunologic tolerance, is maintained
despite the fact that the molecular mechanisms by which
lymphocyte receptor specificities are generated are not
biased to exclude receptors for self antigens. In other
words, lymphocytes with the ability to recognize self
antigens are constantly being generated during the
normal process of lymphocyte maturation. Furthermore,
many self antigens have ready access to the immune
system, so unresponsiveness to these antigens cannot
(APCs) display antigens to T cells does not distinguish
between foreign and self proteins, so self antigens are
normally seen by lymphocytes. It follows that there must
exist mechanisms that prevent immune responses to self
antigens. These mechanisms are responsible for one of
the cardinal features of the immune system—namely,
immune system may attack the individual’s own cells
and tissues. Such reactions are called autoimmunity,
and the diseases they cause are called autoimmune
diseases. In addition to tolerating the presence of self
antigens, the immune system has to coexist with many
and the immune system of a pregnant female has to
accept the presence of a fetus that expresses antigens
Immunologic Tolerance: General Priniciples and
Central T Lymphocyte Tolerance, 178
Peripheral T Lymphocyte Tolerance, 180
Regulation of T Cell Responses by Inhibitory
Immune Suppression by Regulatory T Cells, 184
Deletion: Apoptosis of Mature Lymphocytes, 185
Peripheral B Cell Tolerance, 188
Tolerance to Commensal Microbes and Fetal
Tolerance to Commensal Microbes in the Intestines
Tolerance to Fetal Antigens, 189
Role of Infections and Other Environmental
178 CHAPTER 9 Immunologic Tolerance and Autoimmunity
same mechanisms involved in unresponsiveness to self.
In this chapter we address the following questions:
• How does the immune system maintain unresponsiveness to self antigens?
• What are the factors that may contribute to the loss
of self-tolerance and the development of autoimmunity?
• How does the immune system maintain unresponsiveness to commensal microbes and the fetus?
and the fetus, and how tolerance may fail, resulting in
IMMUNOLOGIC TOLERANCE: GENERAL
Immunologic tolerance is a lack of response to antigens that is induced by exposure of lymphocytes
to these antigens. When lymphocytes with receptors
for a particular antigen encounter this antigen, any of
several outcomes is possible. The lymphocytes may be
response; antigens that elicit such a response are said to
be immunogenic. The lymphocytes may be functionally
inactivated or killed, resulting in tolerance; antigens that
ignore the presence of the antigen. Normally, microbes
are immunogenic and self antigens are tolerogenic.
and the additional signals present when the antigen is
an immune response or tolerance. This experimental
observation has been exploited to analyze what factors
determine whether activation or tolerance develops as a
consequence of encounter with an antigen.
The phenomenon of immunologic tolerance is
important for several reasons. First, as we stated at the
outset, self antigens normally induce tolerance, and
or control unwanted immune reactions. Strategies for
inducing tolerance are being tested to treat allergic and
autoimmune diseases and to prevent the rejection of
organ transplants. The same strategies may be valuable
in gene therapy to prevent immune responses against
the products of newly expressed genes or vectors and
even for stem cell transplantation if the stem cell donor
is genetically different from the recipient.
Immunologic tolerance to different self antigens
may be induced when developing lymphocytes
encounter these antigens in the generative (central)
or peripheral tissues, called peripheral tolerance (Fig.
9.1). Central tolerance is a mechanism of tolerance only
Tolerance to self antigens that are not present in these
organs must be induced and maintained by peripheral
mechanisms. We have only limited knowledge of which
self antigens induce central or peripheral tolerance or
are ignored by the immune system.
T lymphocytes, is discussed first because many of the
mechanisms of self-tolerance were defined by studies of
these cells. In addition, CD4+ helper T cells orchestrate
virtually all immune responses to protein antigens, so
tolerance in these cells may be enough to prevent both
cell-mediated and humoral immune responses against
self proteins. Conversely, failure of tolerance in helper T
cells may result in autoimmunity manifested by T cell–
mediated attack against tissue self antigens or by the
production of autoantibodies against self proteins.
CENTRAL T LYMPHOCYTE TOLERANCE
The principal mechanisms of central tolerance in T
cells are death of immature T cells and the generation
of CD4+ regulatory T cells (Fig. 9.2). The lymphocytes
CHAPTER 9 Immunologic Tolerance and Autoimmunity 179
as a peptide bound to a self major histocompatibility
complex (MHC) molecule, that lymphocyte receives
signals that trigger apoptosis. Thus, the self-reactive cell
dies before it can become functionally competent. This
process, called negative selection (see Chapter 4), is a
major mechanism of central tolerance. The process of
negative selection affects self-reactive CD4+ T cells and
CD8+ T cells, which recognize self peptides displayed by
class II MHC and class I MHC molecules, respectively.
Why immature lymphocytes die upon receiving strong
T cell receptor (TCR) signals in the thymus, while
mature lymphocytes that get strong TCR signals in the
periphery are activated, is not fully understood.
Some immature CD4+ T cells that recognize self
antigens in the thymus with high affinity do not die
but develop into regulatory T cells and enter peripheral
with self antigens in peripheral tissues or suppressed by regulatory T cells.
180 CHAPTER 9 Immunologic Tolerance and Autoimmunity
tissues (see Fig. 9.2). The functions of regulatory T cells
are described later in the chapter. What determines
whether a thymic CD4+ T cell that recognizes a self
antigen will die or become a regulatory T cell is also not
Immature lymphocytes may interact strongly with an
antigen if the antigen is present at high concentrations
in the thymus and if the lymphocytes express receptors
that recognize the antigen with high affinity. Antigens
that induce negative selection may include proteins that
are abundant throughout the body, such as plasma proteins and common cellular proteins.
Surprisingly, many self proteins that are normally
epithelial cells of the thymus. A protein called AIRE
(autoimmune regulator) is responsible for the thymic
expression of these peripheral tissue antigens. Mutations
in the AIRE gene are the cause of a rare disorder called
autoimmune polyendocrine syndrome. In this disorder,
several tissue antigens are not expressed in the thymus
because of a lack of functional AIRE protein, so immature
T cells specific for these antigens are not eliminated and
do not develop into regulatory cells. These cells mature
against the tissue-restricted antigens, which are expressed
normally in the appropriate peripheral tissues even in
the absence of AIRE. Therefore, T cells specific for these
antigens emerge from the thymus, encounter the antigens
in the peripheral tissues, and attack the tissues and cause
disease. It is not clear why endocrine organs are the most
frequent targets of this autoimmune attack. Although
this rare syndrome illustrates the importance of negative
selection in the thymus for maintaining self-tolerance, it
is not known if defects in negative selection contribute to
Central tolerance is imperfect, and some self-reactive
prevent the activation of these lymphocytes.
PERIPHERAL T LYMPHOCYTE TOLERANCE
Peripheral tolerance is induced when mature T cells
recognize self antigens in peripheral tissues, leading
to functional inactivation (anergy) or death, or when
peripheral T cell tolerance is described in this section.
Peripheral tolerance is clearly important for preventing
T cell responses to self antigens that are not present in
the thymus, and it also may provide backup mechanisms
for preventing autoimmunity in situations where central
tolerance to antigens that are expressed in the thymus is
CHAPTER 9 Immunologic Tolerance and Autoimmunity 181
sensitive to suppression by regulatory T cells. As noted
in previous chapters, naive T lymphocytes need at least
antigen, and signal 2 is provided by costimulators that
are expressed on APCs, typically as part of the innate
immune response to microbes (or to damaged host
lymphoid organs are in a resting (or immature) state, in
which they express little or no costimulators, such as B7
proteins (see Chapter 5). These dendritic cells constantly
process and display the self antigens that are present in
the tissues. T lymphocytes with receptors for the self
antigens are able to recognize the antigens and thus receive
signals from their antigen receptors (signal 1), but the T
cells do not receive strong costimulation because there
is no accompanying innate immune response. Thus, the
presence or absence of costimulation is a major factor
determining whether T cells are activated or tolerized.
Anergy in T cells refers to long-lived functional
unresponsiveness that is induced when these cells
recognize self antigens (Fig. 9.4). Self antigens are
normally displayed with low levels of costimulators,
induction, by mechanisms that are described later.
Anergic cells survive but are incapable of responding
The two best-defined mechanisms responsible for the
induction of anergy are abnormal signaling by the TCR
complex and the delivery of inhibitory signals from
receptors other than the TCR complex.
activating signals. In some cases, this is related to the
activation of enzymes (ubiquitin ligases) that modify
signaling proteins and target them for intracellular
182 CHAPTER 9 Immunologic Tolerance and Autoimmunity
CD28 family, cytotoxic T lymphocyte–associated
antigen 4 (CTLA-4, or CD152) or programmed cell
death protein 1 (PD-1, CD279), which were introduced in Chapter 5. Anergic T cells may express
higher levels of these inhibitory receptors, which will
inhibit responses to subsequent antigen recognition.
The functions and mechanisms of action of these
receptors are described in more detail below.
Regulation of T Cell Responses by Inhibitory
Immune responses are influenced by a balance between
engagement of activating and inhibitory receptors.
This idea is established for B and T lymphocytes and
natural killer (NK) cells. In T cells, the main activating
inhibitory receptors, also called coinhibitors, are CTLA-4
and PD-1. The functions and mechanisms of action of
these inhibitors are complementary (Fig. 9.5).
• CTLA-4. CTLA-4 is expressed transiently on activated CD4+ T cells and constitutively on regulatory
T cells (described later). It functions to suppress the
activation of responding T cells. CTLA-4 works by
blocking and removing B7 molecules from the surface
of APCs, thus reducing costimulation by CD28 and
preventing the activation of T cells (see Fig. 9-5A).
The choice between engagement of CTLA-4 or CD28
is determined by the affinity of these receptors for B7
and the level of B7 expression. CTLA-4 has a higher
affinity for B7 molecules than does CD28, so it binds
B7 tightly and prevents the binding of CD28. This
competition is especially effective when B7 levels are
low (as would be expected normally when APCs are
displaying self and probably tumor antigens); in these
situations, the receptor that is preferentially engaged
the ligands will be occupied by CTLA-4 and some B7
will be available to bind to the low-affinity activating
receptor CD28, leading to T cell costimulation.
• PD-1. PD-1 is expressed on CD8+ and CD4+ T cells
phosphorylated upon recognition of its ligands PD-L1
or PD-L2. Once phosphorylated, these tyrosines bind
a tyrosine phosphatase that inhibits kinase-dependent
activating signals from CD28 and the TCR complex
(see Fig. 9-5B). Because the expression of PD-1 on T
cells is increased upon chronic T cell activation and
APC, Antigen-presenting cells.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 183
costimulation by binding to B7 with
Signaling inhibitor of CD28 and TCR:
inhibits kinase-depending signals
Fig. 9.5 Mechanisms of action and properties of cytotoxic T lymphocyte–associated protein 4 (CTLA-4)
184 CHAPTER 9 Immunologic Tolerance and Autoimmunity
expression of the ligands is increased by cytokines
antigenic stimulation. This may happen in responses
to chronic infections, tumors, and self antigens, when
PD-1–expressing T cells encounter the ligand on
infected cells, tumor cells, or APCs.
One of the most impressive therapeutic applications of
receptors. Such treatment leads to enhanced antitumor
immune responses and tumor regression in a significant
fraction of the patients (see Chapter 10). This type of
therapy has been termed checkpoint blockade, because
the inhibitory receptors impose checkpoints in immune
responses, and the treatment blocks these checkpoints
develop autoimmune reactions, consistent with the idea
that the inhibitory receptors are constantly functioning
to keep autoreactive T cells in check. Rare patients with
mutations in one of their two copies of the CTLA4 gene,
which reduce expression of the receptor, also develop
multiorgan inflammation (and a profound, as yet unexplained, defect in antibody production).
Several other receptors on T cells other than CTLA-4
and PD-1 have been shown to inhibit immune responses
and are currently being tested as targets of checkpoint
blockade therapy. Some of these receptors are members
of the tumor necrosis factor (TNF) receptor family or
Immune Suppression by Regulatory T Cells
Regulatory T cells develop in the thymus or peripheral
tissues on recognition of self antigens and suppress
the activation of potentially harmful lymphocytes
specific for these self antigens (Fig. 9.6). The majority
require interleukin-2 (not shown). DC, Dendritic cell; NK, natural killer.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 185
of self-reactive regulatory T cells probably develop in
the thymus (see Fig. 9.2), but they may also arise in
peripheral lymphoid organs. Most regulatory T cells are
CD4+ and express high levels of CD25, the a chain of the
development and function of the cells. Mutations of the
by the acronym IPEX, for immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.
The survival and function of regulatory T cells
are dependent on the cytokine IL-2. This role of IL-2
deleted and in humans with homozygous mutations in
the a or ß chain of the IL-2 receptor. Recall that we
introduced IL-2 in Chapter 5 as a cytokine made by
antigen-activated T cells that stimulates proliferation
of these cells. Thus, IL-2 is an example of a cytokine
that serves two opposite roles: it promotes immune
responses by stimulating T cell proliferation, and it
inhibits immune responses by maintaining functional
regulatory T cells. Numerous clinical trials are testing
the ability of IL-2 to promote regulation and control
harmful immune reactions, such as inflammation in
autoimmune diseases and graft rejection.
The cytokine transforming growth factor ß (TGFß) also plays a role in the generation of regulatory T
cells, perhaps by stimulating expression of the FoxP3
transcription factor. Many cell types can produce
Regulatory T cells may suppress immune responses
• Some regulatory cells produce cytokines (e.g., IL-10,
TGF-ß) that inhibit the activation of lymphocytes,
dendritic cells, and macrophages.
• Regulatory cells express CTLA-4, which, as discussed earlier, may block or remove B7 molecules
made by APCs and make these APCs incapable of
providing costimulation via CD28 and activating T
essential T cell growth factor, thus reducing its availability for responding T cells.
The great interest in regulatory T cells has in part been
regulatory T cell function or the resistance of pathogenic
Deletion: Apoptosis of Mature Lymphocytes
Recognition of self antigens may trigger pathways
of apoptosis that result in elimination (deletion) of
the self-reactive lymphocytes (Fig. 9.7). There are two
likely mechanisms of death of mature T lymphocytes
and activate cytosolic enzymes called caspases that
induce apoptosis. In normal immune responses,
by costimulation and by growth factors produced
during the responses. However, self antigens, which
are recognized without strong costimulation, do not
stimulate production of antiapoptotic proteins, and
the relative deficiency of survival signals induces
death of the cells that recognize these antigens.
receptor that culminate in the activation of caspases and
apoptosis. The best-defined death receptor–ligand pair
involved in self-tolerance is a protein called Fas (CD95),
which is expressed on many cell types, and Fas ligand
(FasL), which is expressed mainly on activated T cells.
Evidence from genetic studies supports the role of
deletion of self-reactive T cells in the thymus and also
in peripheral tissues. Mice with mutations in the fas
and fasl genes and children with mutations in FAS all
signaling, also have similar autoimmune diseases. The
human diseases, collectively called the autoimmune
186 CHAPTER 9 Immunologic Tolerance and Autoimmunity
lymphoproliferative syndrome (ALPS), are rare and
are the only known examples of defects in apoptosis
causing an autoimmune disorder.
former and activation by the latter (Fig. 9.8).
• Self antigens are present in the thymus, where they
induce deletion and generate regulatory T cells; by
contrast, most microbial antigens tend to be excluded
from the thymus because they are typically captured
from their sites of entry and transported into peripheral lymphoid organs (see Chapter 3).
thus favoring the induction of T cell anergy or death, or
suppression by regulatory T cells. By contrast, microbes
proliferation and differentiation into effector cells.
• Self antigens are present throughout life and may
therefore cause prolonged or repeated TCR engagement, again promoting anergy, apoptosis, and the
development of regulatory T cells.
Antigen recognition T cell response
apoptosis of the cells by the death receptor (extrinsic) pathway.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 187
Self polysaccharides, lipids, and nucleic acids are
T-independent antigens that are not recognized by T cells.
These antigens must induce tolerance in B lymphocytes
to prevent autoantibody production. Self proteins may
not elicit autoantibody responses because of tolerance in
helper T cells and in B cells. It is suspected that diseases
When immature B lymphocytes interact strongly with
self antigens in the bone marrow, the B cells either
change their receptor specificity (receptor editing) or
are killed (deletion) (Fig. 9.9).
• Receptor editing. Immature B cells are at a stage of
maturation in the bone marrow when they have rearranged their immunoglobulin (Ig) genes, express IgM
with a heavy chain and light chain, and have shut off
the RAG genes that encode the recombinase. If these
B cells recognize self antigens in the bone marrow,
they may reexpress RAG genes, resume light-chain
gene recombination, and express a new Ig light
chain (see Chapter 4). The heavy chain gene cannot
recombine because some segments are lost during
produce a new antigen receptor that may no longer
recognize the self antigen. This process of changing
receptor specificity, called receptor editing, reduces
the chance that potentially harmful self-reactive B
cells will leave the marrow. It is estimated that 25%
to 50% of mature B cells in a normal individual may
can undergo receptor editing.)
• Deletion. If editing fails, immature B cells that
strongly recognize self antigens receive death signals
As in the T cell compartment, negative selection of
B cells eliminates lymphocytes with high-affinity
receptors for abundant, and usually widely expressed,
cell membrane or soluble self antigens.
Feature of antigen Tolerogenic self antigens Immunogenic foreign antigens
mechanisms of central tolerance
Deficiency of costimulators may
lead to T cell anergy or apoptosis,
sensitivity to suppression by Treg
(throughout life); prolonged TCR
Presence in blood and peripheral
tissues (most microbial antigens)
permits concentration in peripheral
Short exposure to microbial antigen
reflects effective immune response
immune responses. TCR, T cell receptor; Treg, T regulatory cells.
188 CHAPTER 9 Immunologic Tolerance and Autoimmunity
• Anergy. Some self antigens, such as soluble proteins,
may be recognized in the bone marrow with low
avidity. B cells specific for these antigens survive, but
antigen receptor expression is reduced, and the cells
become functionally unresponsive (anergic).
Mature B lymphocytes that encounter self antigens
in peripheral lymphoid tissues become incapable
of responding to that antigen (Fig. 9.10). According
cells have been eliminated or are tolerant), the B cells
become anergic because of a block in signaling from
the follicles. These excluded B cells may die because
they do not receive necessary survival stimuli. B cells
that recognize self antigens in the periphery may also
undergo apoptosis, or inhibitory receptors on the B
cells may be engaged, thus preventing activation. As
mentioned earlier, regulatory T cells may also contribute to B cell tolerance.
TOLERANCE TO COMMENSAL MICROBES
Before concluding our discussion of the mechanisms of
immunologic tolerance, it is useful to consider two other
types of antigens that are not self but are produced by
cells or tissues that have to be tolerated by the immune
system. These are products of commensal microbes that
live in symbiosis with humans and paternally derived
antigens in the fetus. Coexistence with these antigens is
dependent on many of the same mechanisms that are
used to maintain peripheral tolerance to self antigens.
Tolerance to Commensal Microbes in the
to be almost 10 times the number of nucleated human
cells, prompting microbiologists to point out that we are
only 10% human and 90% microbial!). These microbes
reside in the intestinal and respiratory tracts and on the
skin, where they serve many essential functions. For
potentially harmful organisms. Mature lymphocytes in
these tissues are capable of recognizing the organisms
but do not react against them, so the microbes are not
eliminated, and harmful inflammation is not triggered.
Fig. 9.10 Peripheral tolerance in B lymphocytes. A mature
that antigen (anergy), or it dies by apoptosis (deletion), or its
activation is suppressed by engagement of inhibitory receptors.
Fig. 9.9 Central tolerance in immature B lymphocytes. An
apoptosis (negative selection, or deletion), or reduces antigen
receptor expression and becomes functionally unresponsive.
CHAPTER 9 Immunologic Tolerance and Autoimmunity 189
In the gut, several mechanisms account for the inability
of IL-10–producing regulatory T cells, and an unusual
property of intestinal dendritic cells such that signaling
from some Toll-like receptors leads to inhibition rather
than activation. In addition, many commensal bacteria
tolerance to commensal bacteria in the skin are not as
The evolution of placentation in eutherian mammals
allowed the fetus to mature before birth but created the
problem that paternal antigens expressed in the fetus,
which are foreign to the mother, have to be tolerated by
is strongly correlated with the ability to generate stable
peripheral regulatory T cells. It is unclear whether women
who suffer recurrent pregnancy losses have a defect in
the generation or maintenance of these regulatory T cells.
Other mechanisms of fetal tolerance include exclusion of
Now that we have described the principal mechanisms of immunologic tolerance, we consider the
consequences of the failure of self-tolerance—namely,
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