1. Ignorance
     Immunoprivileged organs  

2. Antigen-specific mechanisms
     Clonal deletion and Treg conversion    Suppression    Induced anergy  

3. Split tolerance

4. References

Mechanisms of peripheral tolerance include direct inactivation of effector T cells by either clonal deletion, conversion to regulatory T cells (Tregs) or induction of anergy.^[1] Tregs, which are also generated during thymic T cell development, further suppress the effector functions of conventional lymphocytes in the periphery.^[2] Dependence of a particular antigen on either central or peripheral tolerance is determined by its abundance in the organism.^[3] B cell peripheral tolerance is much less studied and is largely mediated by B cell dependence on T cell help.

Ignorance

Antigens, which are present in generally low amount can be ignored by the immune system without any further mechanism, since T cells have to be activated, prior to their migration to non-lymphoid tissues.^[3][4] Specialized mechanisms ensuring ignorance by immune system have developed in so called immunoprivileged organs.^[1]

Immunoprivileged organs

Potentially self-reactive T-cells are not activated at immunoprivileged sites, where antigens are expressed in non-surveillanced areas. This can occur in the testes, for instance. Anatomical barriers can separate the lymphocytes from the antigen, an example is the central nervous system (the blood-brain-barrier). Naive T-cells are not present in high numbers in peripheral tissue, but stay mainly in the circulation and lymphoid tissue.

Some antigens are at too low a concentration to cause an immune response – a subthreshold stimulation will lead to apoptosis in a T cell.

These sites include the brain, the anterior chamber of the eye, the testes and the fetus. These areas are protected by several mechanisms:

Fas-ligand expression binds Fas on lymphocytes inducing apoptosis, anti-inflammatory cytokines (including TGF-beta and interleukin 10) and blood-tissue-barrier with tight junctions between endothelial cells.

In the placenta indoleamine 2,3-dioxygenase (IDO) breaks down tryptophan, creating a "tryptophan desert" micro environment which inhibits lymphocyte proliferation.

Antigen-specific mechanisms

Although the majority of self-reactive T cell clones are deleted in the thymus by the mechanisms of central tolerance, low affinity self-reactive T cells continuously escape to the immune periphery.^[3] Therefore, additional mechanisms exist to remove self-reactive T cells from the repertoire in the immune periphery.

Clonal deletion and Treg conversion

Aside from dendritic cells, additional cell populations were identified that are able to induce antigen-specific T cell tolerance. These are mainly the members of lymph node stromal cells (LNSCs). LNSCs are generally divided into several sub-populations based on the expression of gp38 (PDPN) and CD31 surface markers.^[8] Among those, only fibroblastic reticular cells and lymph node stromal cells were shown to play a role in the peripheral tolerance. Both of those populations are able to induce CD8 T cell tolerance by presentation of the endogenous antigens on MHCI molecules ^[9][10] and even the CD4 T cell tolerance by the presentation of the peptide-MHCII complexes, which they acquired from the DCs.^[11]

Suppression

Another mechanism which protects the body from autoimmune reactions is the suppression of self-reactive effector T cells by Tregs. Tregs can be generated either in the thymus during the negative selection or in the immune periphery by the mechanisms described above. Those generated in the thymus are called natural Tregs (nTregs) and the ones generated in the periphery are called induced Tregs (iTregs). Regardless of their origin, once present Tregs use several different mechanisms to suppress autoimmune reactions. These include depletion of IL-2 from the environment and secretion of tolerogenic cytokines IL-10 and TGF-β.^[2]

Induced anergy

T-cells can be made non-responsive to antigens presented if the T-cell engages an MHC molecule on an antigen presenting cell (signal 1) without engagement of costimulatory molecules (signal 2). Co-stimulatory molecules are upregulated by cytokines in the context of acute inflammation. Without pro-inflammatory cytokines, co-stimulatory molecules will not be expressed on the surface of the antigen presenting cell, and so anergy will result if there is an MHC-TCR interaction between the T cell and the APC.^[1]

Split tolerance

Since many pathways of immunity are interdependent, they do not all need to be tolerised. For example, tolerised T cells will not activate autoreactive B cells. Without this help from CD4 T cells, the B cells will not be activated.^[5]

References

• Dan Starkey (series)
• Dan Starkey series
• Dan Station
• Dan Stec
• Dan Stephen Palami
• Dan Sterup-Hansen
• Dan Stevenson (Indiana politician)
• Dan Stiles
• Danstown, West Virginia
• Dan Straily
• Dan Strugnell
• Dan Stuart
• Dan Sudick
• Dan Sullivan (Alaska)
• Dan Sullivan (Alaska politician, born 1964)
• Dan Sullivan (Arkansas politician)
• Dan Sullivan (ice hockey)
• Dan Sullivan (ice hockey, born 1987)
• Dan Sullivan (mayor)
• Dan Sullivan (politician)
• Dan Sullivan (politician, born 1951)
• Dan Sullivan (politician, born 1964)
• Dan Sullivan (senator)
• Dan Sullivan (United States Senator, Alaska)
• Dan Sullivan (United States Senator, R-AK)