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T-cell Tolerance
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
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
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?
AIRE
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
In the absence of the AIRE, T cells reactive to tissue-specific antigens mature and leave the thymus
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.
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
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
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
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
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
Peripheral Tolerance
Failure to Encounter Self Antigens
Immunosuppressive factors
• Nuropeptides
• TGFβ
• indoleamine 2 3-dioxygenase
expression of FasL and PDL-1
Kuby immunology 4th
edition
Figure14.8 Immunobiology ,7ed, Garland science
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)
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
Origin of regulatory T cells
tTreg
nTreg
Peripheral tolerance of CD8+T
• More research should be held
• Without co-stimulator molecules and T helper they can convert into anergic cells
• Exhaustion