Peripheral tolerance

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.

Dendritic cells (DCs) are a major cell population responsible for the initiation of adaptive immune response.[1] However, immature DCs are able to induce both CD4 and CD8 tolerance. These immature DCs acquire the antigen from the peripheral tissues (by endocytosis of apoptotic cells) and present it to the naive T cells in the secondary lymphoid organs. If the T cell recognizes the antigen, it is either deleted or converted to Treg.[6] Furthermore, BTLA⁺ DCs were identified as a specialized population of antigen presenting cells (APCs), responsible for Treg conversion.[7] Nonetheless, upon maturation (for example during the infection) DCs largely lose their tolerogenic capabilities.[6]

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]

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.[3]

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.[2]