Central tolerance

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The process is required due to the random generation of receptor specificities that occurs during T cell and B cell differentiation, whereby a proportion of the cells generated are self-reactive (recognise the component self antigens of the host).

In mammals the process occurs in the thymus (T cells) and bone marrow (B cells), when maturing lymphocytes are exposed to self antigens. Self antigens are present in both organs due to endogenous expression within the organ and importation of antigen due to circulation from peripheral sites. In the case of T cell central tolerance, additional sources of antigen are made available in the thymus by the action of the transcription factor AIRE.

After exposure to self antigens, T cells and B cells become immunologically tolerant (non-reactive) in a number of ways :

• Negative selection (apoptosis)
• Anergy (non-responsiveness)
• Receptor editing (changing the specificity of the autoreactive cell)
• Division to a regulatory lineage

Genetic defects in these processes lead to autoimmunity, such as in the human syndromes APS-1 and IPEX.