Negative selection (immunology)

Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self. The concept of central tolerance was proposed in 1959 by Joshua Lederberg, as part of his general theory of immunity and tolerance, and is often mistakenly attributed to MacFarlane Burnet. Lederberg hypothesized that it is the age of the lymphocyte that defines whether an antigen that is encountered will induce tolerance, with immature lymphocytes being tolerance sensitive. Lederberg's theory that self-tolerance is 'learned' during lymphocyte development was a major conceptual contribution to immunology, and it was experimentally substantiated in the late 1980s when tools to analyze lymphocyte development became available. Central tolerance is distinct from peripheral tolerance in that it occurs while developing immune cells are still present in the primary lymphoid organs (the thymus and bone-marrow), prior to export into the periphery. Such peripheral tolerance is generated after the cells reach the periphery by regulatory T cells. Such regulatory T cells can be considered both central tolerance and peripheral tolerance mechanisms, as they can be generated from self(or foreign)-reactive T cells in the thymus (during T cell differentiation), but can also exert immune suppression in the periphery on other self(or foreign)-reactive T cells.

At first, all T and B cell precursors have an identical genome, but then receptor variety is generated by a combination of 3 mechanisms. The first mechanism is the combination of the alpha- and beta-chain for the T cell receptor (TCR), or of the heavy and light chain for the B cell receptor (BCR), each encoded by 2 different gene copies - the unused copy gets inactivated. T cell and B cell receptor genes contain multiple gene segments (the V, D, and J segments) which need to be physically rearranged 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 junctional diversity - and gives rise to the complementarity determining regions (CDR). These random 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 junctional 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).

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