Central Tolerance - Requirement For Central Tolerance

Requirement For Central Tolerance

Central tolerance for T cells is induced in the thymus, where developing thymocytes (T cells in thymus) that recognize self-peptide–MHC complexes with too high affinity are deleted. For B cells the central tolerance is executed in the bone marrow (the B cell receptor the membrane bound version of antibodies). First all T and B cell precursors have an identical genome, but then the variety of receptors is generated by the combination of 3 mechanisms. The first mechanism is the combination of the alpha and beta-chain for the TCR or of the heavy and light chain for the BCR each encoded by 2 different gene copies - the not used copy gets inactivated.The T cell receptor and B cell receptor genes contain multiple gene segments (the V, D, J - segments) which need to be physically rearranged together by somatic gene rearrangement - called V(D)J-Recombination - to make a functional gene. At the site of segment recombination additional bases will be inserted which results in additional Diversity - called the junctional Diversity - and gives rise to the complementary determining regions (CDR). These random Generation of Diversity combinations and base insertions allow the creation of T cell receptors and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens. Conversely, the random nature of the Generation of Diversity creates, by chance, a population of T cells and B cells that are self-reactive (i.e., recognize an antigen which is a constituent component of the host).

In mammals the process occurs in the thymus (T cells) and bone marrow (B cells). These are the two primary lymphoid organs where T cells and B cells mature. During the maturation phases of both T cells and B cells the cells are sensitive to antigen-recognition. Unlike mature peripheral lymphocytes, which become activated upon encountering their specific antigen, the immature lymphocytes respond to stimulation with antigen by undergoing a rewiring of the cellular processes. The response to antigen at this stage depends on the properties of the antigen, the cell type and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), altering its antigen receptor (receptor editing) or entering a regulatory lineage.

As this tolerance is dependent on encountering the self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs. In the case of B cells in the bone marrow, this is limited to ubiquitous and bone-marrow specific antigens present in the bone-marrow and additional antigens imported by circulation (either as raw antigens or presented by circulating dendritic cells). The thymus has an additional source of antigen through the action of the transcription factor AIRE, which allows the expression of organ-specific antigens such as insulin in the thymus.