Immunological Tolerance

Immunological tolerance is the state of unresponsiveness

to a particular antigen (that is induced by previous
exposure to that antigen)which is primarily established in
T- and B-lymphocytes.

The clonal receptors of lymphocytes are generated by

random recombination of the many genes that code for
the antigen binding regions.

This creates the need to sort out dangerous receptors that

could recognize and destroy self tissues.

The breakdown of immunological tolerance to self-

antigens is the cause of autoimmune diseases.
Central tolerance refers to the selection processes which
T cell precursors undergo in the thymus before they are
released as mature naive T cells.

Those T cell precursors that respond strongly to the self-

antigens presented in the thymus undergo apoptosis. This
is called negative selection.
Peripheral tolerance refers to the diverse mechanism
that enforce and maintain T-cell tolerance outside the
thymus.

These include

the prevention of contact between auto-reactive T-

cells and their target antigens (immunological
ignorance)

the peripheral deletion of auto-reactive T-cells by

activation induced cell death or cytokine withdrawal

the incapacity of T cells to mount effector responses

upon recognizing their target antigen (anergy)

and the suppression of immune responses by

B cell tolerance is established by several mechanisms
including clonal deletion of auto reactive B cells, mostly in
the bone marrow.

In addition B-cell tolerance is maintained by tolerant T

cells. The production of high-affinity class-switched
antibodies depends on T-cell help.

Therefore, if tolerance to a particular antigen is firmly

established in the T-cell compartment, B-cells that
recognize this antigen will usually remain tolerant.

To overcome immunological tolerance is one major goal

for innovative treatments against cancer.
Antigens that induce tolerance are called toIerogens, or
tolerogenic antigens, to distinguish them from
immunogens, which generate immunity.

A single antigen may be an immunogen or a tolerogen

depending
on how it is recognized by specific lymphocytes.

Tolerance to self antigens, also called self-tolerance, is a

fundamental property of the normal immune system.
 Immunological tolerance is important for
several reasons:
Normal individuals are tolerant of their own (self)
antigens because the lymphocytes that recognize self
antigens are killed or inactivated, or change their
specificity.
All individuals inherit the same antigen receptor genes,
and these genes recombine randomly and are expressed
in lymphocytes without influencing by what is foreign or
self.

During this process, some developing T and B cells in

every individual may express receptors capable of
recognizing self antigens and causing damage.

The mechanisms of immunologic tolerance are designed

to prevent such reactions.
Normal individuals are tolerant of their own (self) antigens
because the lymphocytes that recognize self antigens are
killed or inactivated, or change their specificity.
Foreign antigens may be administered in ways
that inhibit immune responses by inducing
tolerance in lymphocytes.
Some microbes and tumors may evade immune attack by
inducing unresponsiveness in specific lymphocytes.

Many of the mechanisms of tolerance to foreign antigens

are similar to those of self-tolerance in mature
lymphocytes.

Effective immunization methods are designed to enhance

the immunogenicity of antigens by administering them in
ways that promote lymphocyte activation and prevent
tolerance induction.
The induction of immunological tolerance may
be exploited as a therapeutic approach for
preventing harmful immune responses

Tolerance induction may also be useful for preventing

immune reactions to the products of newly expressed
genes in gene therapy protocols and preventing reactions
to injected proteins in patients with deficiencies of these
proteins (e.g., hemophiliacs treated with factor VIII).
GENERAL FEATURES AND MECHANISMS OF
IMMUNOLOGICAL TOLERANCE
There are several characteristics of self-tolerance in T
and B lymphocyte populations, and many of these are
also features of tolerance to foreign antigens:
Tolerance results from the recognition of
antigens by specific lymphocytes.

Self-tolerance may be induced in immature self

reactive lymphocytes in generative lymphoid
organs (central tolerance), or in mature
lymphocytes in peripheral sites (peripheral
tolerance)
Central tolerance ensures that lymphocytes cannot
recognize self antigens that are present in the generative
lymphoid organs.

However, central tolerance cannot account for

unresponsiveness to antigens that are expressed only in
peripheral tissues. Tolerance to such tissue specific self
antigens is maintained by peripheral mechanisms.
Central tolerance occurs because during their
maturation in the generative lymphoid organs, all
lymphocytes pass through a stage in which encounter
with antigen leads to cell death or the expression of new
antigen receptors or a change in functional capabilities.

The only antigens normally present in the thymus and

bone marrow are self antigens because foreign antigens
that enter from the external environment are not
transported to the thymus but rather are captured and
transported to peripheral lymphoid organs, such as the
lymph nodes, spleen, and mucosal lymphoid tissues.

Therefore, in the generative lymphoid organs, developing

lymphocytes normally encounter only self antigens at
high concentrations.
This interaction of immature lymphocytes with self
antigens has several possible outcomes-the cells may die
by apoptosis (called clonal deletion);

many immature B cells do not die but change their

receptors and stop recognizing the self antigen (called
receptor editing);

and some CD4+T cells differentiate into regulatory T cells,

which migrate to the periphery and prevent responses to
the self antigens.

Both clonal deletion and receptor editing represent

mechanisms of negative selection during lymphocyte
development.
Peripheral tolerance occurs when mature
lymphocytes that recognize self antigens become
incapable of responding to that antigen, or lose
their viability and become short-lived cells, or are
induced to die by apoptosis.
Peripheral tolerance is most important for maintaining
unresponsiveness to self antigens that are expressed in
peripheral tissues and not in the generative lymphoid
organs, and for tolerance to self antigens that are
expressed in adult life, after mature lymphocytes have
been generated.
Some self antigens may be ignored by the
immune system, so that lymphocytes encounter
the self antigen but fail to respond in any
detectable way and remain viable and
functional.
 T LYMPHOCYTE TOLERANCE

Tolerance in CD4+ helper T lymphocytes is an effective

way of preventing immune responses to protein antigens
because helper T cells are necessary inducers of both cell-
mediated and humoral immune responses to proteins.
 Central Tolerance in T Cells
During their maturation in the thymus, many immature
T cells that recognize antigens with high avidity are
deleted.

If immature thymocytes with high-affinity receptors

encounter self antigens in the thymus, one result is
apoptotic death of the cells.

This process affects both class I and class II MHC-

restricted T cells and is therefore important for tolerance
in both CD+8and CD4+ lymphocyte populations.
 Peripheral T Cell Tolerance

Mature T cells that recognize self antigens in peripheral

tissues become incapable of subsequently responding to
these antigens.

Peripheral tolerance mechanisms are responsible for T cell

tolerance to tissue-specific self antigens that are not
abundant in the thymus.

The same mechanisms may induce unresponsiveness to

tolerogenic forms of foreign antigens. Peripheral tolerance
is due to anergy, deletion, or suppression of T cells.
Anergy (Functional Unresponsiveness) Induced by
Recognition of Self Antigen

Exposure of CD4+" T cells to an antigen in the absence of

costimulation or innate immunity may make the cells
incapable of responding to that antigen.

Full activation of T cells requires the recognition of

antigen by the TCR (signall) and recognition of
costimulators, mainly B7-1 and B7-2, by CD28 .

Anergy results from biochemical or genetic alterations

that reduce the ability of lymphocytes to respond to self
antigens
Dendritic cells that are resident in lymphoid organs and
nonlymphoid tissues may present self antigens to T
lymphocytes and maintain tolerance.

Tissue dendritic cells are normally in a resting (immature)

state and express few or no co stimulators. Such APCs
may be constantly presenting self antigens without
activating signals, and T cells that recognize these
antigens become anergic.

Thus, dendritic cells that are activated by microbes are

the principal APCs for initiating T cell responses , whereas
resting dendritic cells may be tolerogenic.
 Factors That Determine the Tolerogenicity of
Self Antigens
Self antigens have special properties that make them tolerogenic.
Some self antigens are present at high concentrations in the
generative lymphoid organs, and these antigens may induce negative
selection or the development of regulatory T cells.

In the periphery, self antigens are normally displayed to the immune

system without inflammation or innate immunity.

Under these conditions. APCs express few or no costimulators, and

antigen recognition may either elicit no response (ignorance) or
induce anergy or cell death.

Because self antigens cannot be eliminated, they are capable of

chronically engaging the antigen receptors of specific T lymphocytes,
and chronic stimulation without activating signals may induce anergy
or activation-induced cell death or promote the development of
regulatory T cells.
B LYMPHOCYTE TOLERANCE

Tolerance in B lymphocytes is necessary for maintaining

unresponsiveness to thymus-independent self antigens, such as
polysaccharides and lipids.

B cell tolerance also plays a role in preventing antibody responses to

protein antigens.
 Central Tolerance in B Cells

Immature B lymphocytes that recognize self antigens in

the bone marrow with high affinity either change their
specificity or are deleted.

If immature B cells recognize self antigens that are

present at high concentration in the bone marrow then B
cell acquiring a new specificity. This process is called
receptor editing and is an important mechanism for
eliminating self-reactivity from the mature B cell
repertoire.

If editing fails to eliminate auto reactivity, the immature

B cells may be deleted (Le., they die by apoptosis).

Weaker recognition of self antigens may lead to functional

 Peripheral B Cell Tolerance

Mature B lymphocytes that recognize self antigens in

peripheral tissues in the absence of specific helper T cells
may be rendered functionally unresponsive or die by
Apoptosis .

Encounter with self antigens reduces B cell survival and

promotes death

B cells that encounter self antigens in the periphery are

less able to migrate into lymphoid follicles than are
normal, naive B cells.
Self-Tolerance in T and B Lymphocytes