I summarized general concepts of T-cell tolerance.

1. T-cell Tolerance

2. CentralTolerance
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

3. CentralTolerance
SomeT cells bind to
epitopes tightly
They are deleted by
apoptosis
Negative
selection
SurvivedT cells leave thymus
and migrate throughout the
immune system

4. CentralTolerance
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?

5. AIRE

6. 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-reactiveT cells

7. In the absence of the AIRE,T cells reactive to tissue-
specific antigens mature and leave the thymus

10. PeripheralTolerance
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.

11. PeripheralTolerance
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 RegulatoryT Cells

12. PeripheralTolerance
• 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

13. PeripheralTolerance
• 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
AlthoughT cells encounter self antigens in
body tissues, they will not respond unless they
receive a second signal

16. PeripheralTolerance
• 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

17. PeripheralTolerance
• 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

18. PeripheralTolerance
Failure to Encounter Self Antigens
Immunosuppressive factors
• Nuropeptides
• TGFβ
• indoleamine 2 3-dioxygenase
expression of FasL and PDL-1

19. Kuby immunology 4th
edition

20. Figure14.8 Immunobiology ,7ed, Garland science

21. PeripheralTolerance
• 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)

23. PeripheralTolerance
• 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

24. Origin of regulatoryT cells
tTreg
nTreg

26. Peripheral tolerance of CD8+T
• More research should be held
• Without co-stimulator molecules andT helper they can convert into anergic cells
• Exhaustion