Development of the immunologic tolerance

The recognition of what is « foreign » and what belongs to ones « own » body is a fundamental property of the immune system. The achieving of this self-tolerance occurs mainly during the T cell maturation in the thymus. Surprisingly, 95% of all the cells formed there die before they are ready to mature and emigrate into the peripheral lymphatic organs. This wastefulness is due to the extremely stringent selection criteria that are applied to the T cells that develop in the thymus. This way it is made sure that only T cells with potentially useful receptors survive. Although a few self-reacting B cells are also eliminated during their development, the main mechanism of self tolerance proper lies nevertheless in the elimination of developing, self-reacting T cells in the thymus.

T cells, possessing receptors which strongly bind onto one of the body's own peptides bound to an endogenous MHC molecule, are triggered to undergo apoptosis. Because most B cells require the support of helper T cells for their antigen reactions, the elimination of self-reacting helper T cells also has the result that self-reacting B cells are harmless. The repertoire of T cells thus consists of a combination of positive and negative selection processes.


Positive selection

T cells that – during their development in the thymus – recognize peptides in a complex with the body's own MHC molecules, but do not bind strongly, are selected positively, which is advantageous to the body. The remaining T cells that do not fulfill this selection criterion, i.e., they bind too strongly or do not even recognize MHC molecules, already die during their development through apoptosis.

Despite this positive selection a massive problem remains unsolved: When developing T cells recognize endogenous peptides that are associated with the body's own MHC molecules, mature in the thymus and would emigrate into the peripheral lymphoid tissue, they would cause a devastation in the body because again and again the bodily waste products are transported to cell surfaces via MHC complexes. In order to avoid this deleterious effect a second, negative selection process must take place in the thymus.

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Maturation phases of the T-lymphocytes (interactive diagram).


Negative selection

As with the positive selection, the negative selection also needs the interaction of a T cell receptor with one of the body's own MHC molecule. In contrast to positive selection, which primarily occurs on the epithelial cells of the thymus, the negative selection happens especially on the surface of other cells, e.g., dendritic cells or macrophages. T cells, which strongly bind to the body's own MHC molecules presenting own peptides, are eliminated thereby. Only when the T cells have successfully gone through these two selection steps, do they begin to circulate in the blood as immunocompetent cells and colonize the secondary lymph organs.

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In the periphery the T lymphocytes recognize foreign proteins with the help of MHC molecules (cytotoxic and helper cells recognize MHC molecules).