18/02/2020

Immunological Tolerance
Dr. Barasa
18022020

Learning Objectives
By the end of this lecture the learner should be able to:

• Define immunological tolerance

• Outline the factors that affect tolerogenicity of an
antigen
• Describe the mechanisms of tolerance induction

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Immunological Tolerance
• A state of unresponsiveness that is specific for a
particular antigen
• Induced by prior exposure to that antigen
E.g. to food antigens, air-borne antigens
• Tolerogens: antigens that induce tolerance

The strict definition of immunological tolerance occurs

when an immunocompetent host fails to respond to an
immunogenic challenge with a specific antigen

Self Tolerance
• Prevents the body from mounting an immune attack
against its own tissues

• Loss of self-tolerance leads to destruction of self tissues

- autoimmune disease

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Factors Affecting Tolerogenicity of an Antigen

Structure of antigen (Physical form)

• Large, aggregated, complex molecules are properly

processed and favour an immune response

• Soluble, simple, small molecules are not processed

and favour tolerance

Factors Affecting Tolerogenicity of an Antigen

Antigen dosage
• Optimal dose favours an immune response
• Very large or very small doses favour tolerance

Route of administration
• SQ or IM favour an immune response
• Oral (& at times IV) route favours tolerance

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Mechanisms of Tolerance Induction

Central tolerance
Established in lymphocytes developing in central
lymphoid organs

Peripheral tolerance
Acquired by mature lymphocytes in the peripheral tissues
(after leaving the primary lymphoid organs)

Mechanisms of Central T cell Tolerance

Clonal deletion

• Positive selection – preliminary selection of cells for

survival and their subsequent commitment to a
particular lineage (recognition of MHC class I or II)

• Negative selection - deletion of self-reactive clones of T

cells that interact strongly with MHC/self antigen

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Mechanisms of Peripheral T cell Tolerance

Antigen sequestration/Privileged sites

• Self-antigens are sequestered away from the immune
system by physical or immunological barriers
• They are not processed by functional APCs, and are
therefore not available to T lymphocytes (Clonal
ignorance)
• Brain, anterior chamber of eye, testes
• Dampened inflammatory responses in these organs – T
cell response to self-antigen prevented by Fas (causes
apoptosis) or cytokines (TGFβ, IL-10)

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Mechanisms of Peripheral T cell Tolerance

Clonal anergy
Naïve T cells require 2 signals to
proliferate & differentiate:
• TCR recognition of the
appropriate peptide-MHC
complex
• Expression of co-stimulatory
molecules by APCs – CD80
(B7.1) and CD86 (B7.2)
Autoreactive T cells, when
exposed to antigenic peptides
which do not possess co-
stimulatory molecules, become
anergic to the antigen (functional
unresponsiveness)

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Mechanisms of Peripheral T cell Tolerance

Immune regulation
• Regulatory T cells (Treg) inhibit
the activation & proliferation of
other T cells (& B cells)
• Suppress immune responses of
T & B cells, either directly or by
production of cytokines, most
importantly, TGF-b & IL-10
• Main mechanism of
suppression seems to be the
inhibition of IL-2 transcription in
the responder T cell population

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Mechanisms of Central B cell Tolerance

Alteration of the variable regions to change the specificity

of the surface receptor
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Mechanisms of Peripheral B cell Tolerance

Clonal anergy
• B-cell stimulation in absence of T-
cell help leads to anergy
• When B cells are exposed to
large amounts of soluble Ag they
down regulate their surface IgM &
become anergic
• They also up-regulate the Fas
molecules on their surface
• Interaction of B cells with Fas-
ligand-bearing cells results in
their death via apoptosis

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Mechanisms of Peripheral B cell Tolerance

Anti-idiotype antibodies

• Respond to the unique receptors of B lymphocytes

• Prevent the receptor from combining with antigen
• Therefore shut off antigen-specific responses

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Mechanisms of Peripheral B cell Tolerance

The spleen eliminates unwanted B cells (negative

selection) by:

• Inducing anergy
• Preventing migration into B cell follicles
• Cell death

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