immunological tolerance by arad boustan
TRANSCRIPT
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T-cell Tolerance
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Central Tolerance
In the thymus, the epitopes recognized by these receptors consist of:
• a small molecule, usually a peptide of 6–8 amino acids derived from body proteins; that is, "self" proteins nestled in
• a histocompatibility molecule (encoded by the MHC)• class II for CD4+ T cells
• class I for CD8+ T cells
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Central Tolerance
Some T cells bind to epitopes tightly
They are deleted by apoptosis
Negative selection
Survived T cells leave thymus and migrate throughout the
immune system
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Central Tolerance
There are many proteins that are expressed only in differentiated cells that are restricted to a particular tissue e.g., the insulin-producing beta cells in the islets of Langerhans in the pancreas. How is central tolerance to these proteins achieved
in the thymus?
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AIRE
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Individual organs of the body express tissue specific antigens
retina
ovaries
In the thymus, T cells arise capable of recognizing tissue-specific antigens
Under control of the AIRE protein, thymic modullary cells express tissue specific proteins deleting tissue-reactive T cells
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In the absence of the AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus
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Peripheral Tolerance
The T cells that leave the thymus are relatively — but not completely — safe. Some will have receptors (TCRs) that can respond to self antigens
• that are present in such high concentration that they can bind to "weak" receptors;
• that they may not have encountered in the thymus.
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Peripheral Tolerance
1. Negative Selection in the Peripheral Immune System
2. Lack of Co-stimulation
3. Failure to Encounter Self Antigens
4. Receipt of Death Signals
5. Control by Regulatory T Cells
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Peripheral Tolerance
• Negative Selection in the Peripheral Immune System
AIRE is also active in some antigen-presenting cells in the organs of the
peripheral immune system, e.g., lymph nodes and spleen. So any potentially
autoreactive T cells that failed to be eliminated in the thymus can be selected
against in these tissues
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Peripheral Tolerance
• Lack of Co-stimulation
In order to become activated, the T cell must not only bind to the epitope (MHC-peptide) with its TCR but also receive a second signal from the APC. The receipt of this second signal is called co-stimulation. Among the most important of these co-stimulators are molecules on the APC designated B7 and their ligand on the T cell designated CD28. The binding of CD28 to B7 provides the second signal needed to activate the T cell
Although T cells encounter self antigens in body tissues, they will not respond unless they
receive a second signal
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Peripheral Tolerance
• Lack of Co-stimulation
Most of the time, the cells presenting the body's own antigens either
• fail to provide signal two
• transmit an as-yet-unidentified second signal that turns the T cell into a Regulatory T cell (Treg) that suppresses immune responses.
In either case, self-tolerance results
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Peripheral Tolerance• Failure to Encounter Self Antigens
Some tissues are hidden behind anatomical barriers that keep T cells from reaching them. Examples of such privileged sites
• interior of the eye
• testes
• the brain
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Peripheral Tolerance
Failure to Encounter Self Antigens
Immunosuppressive factors
• Nuropeptides
• TGFβ
• indoleamine 2 3-dioxygenase
expression of FasL and PDL-1
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Kuby immunology 4th
edition
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Figure14.8 Immunobiology ,7ed, Garland science
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Peripheral Tolerance
• Receipt of Death Signals
Some cells of the body express the Fas ligand, FasL. Activated T cells always express Fas. When they encounter these cells, binding of Fas to FasL triggers their death by apoptosis
Lack of Fas Autoimmune Lymphoproliferative Syndrome(ALPS)
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Peripheral Tolerance
• Control by Regulatory T Cells
A minor population of CD4+ T cells, called regulatory T cells (Treg), suppresses the activity of other T cells. They may be important players in protecting the body from attack by its other T cells.
IPEX
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Origin of regulatory T cells
tTreg
nTreg
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Peripheral tolerance of CD8+T
• More research should be held
• Without co-stimulator molecules and T helper they can convert into anergic cells
• Exhaustion