Immune Tolerance - Central Tolerance

Central Tolerance

Central tolerance occurs during lymphocyte development and operates in the thymus and bone marrow. Here, T and B lymphocytes that recognize self antigens are deleted before they develop into fully immunocompetent cells, preventing autoimmunity. This process is most active in fetal life, but continues throughout life as immature lymphocytes are generated.

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.

Positive selection occurs first when naive T-cells are exposed to antigens in the thymus. T-cells which have receptors with sufficient affinity for self-MHC molecules are selected.many self protein antigens are processed and presented by thymic antigen presenting cells (APCs)in association with self MHC. Other cells that do not show sufficient affinity to self-antigens will undergo a deletion process known as death by neglect which involves apoptosis of the cells. The positive selection is a classical example of the importance of some degree of autorreactiveness. This does not occur in B cells.

Negative selection of T-cells with a very high affinity of self-MHC molecules are induced to anergy, or lineage divergence to form T-regulatory cells. This process also occurs during B cell development.