Peripheral tolerance is immunological tolerance developed after autoreactive T and B cells mature and enter the periphery. These include the suppression of autoreactive cells by 'regulatory' T cells (Tregs) and the generation of hyporesponsiveness (anergy) in lymphocytes which encounter antigen in the absence of the co-stimulatory signals that accompany inflammation, or in the presence of co-inhibitory signals.
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.
Immunologically privileged areas
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.
As 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.
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 and antigen presenting cell.
Auto-reactive T cells are inhibited by CD25 regulatory T cells. Experimentally, removal of regulatory T cells leads to autoimmune reactions.