Immunological tolerance by Arad Boustan

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