To function properly, the T cells must have two traits: (1) They must be able to recognize the major histocompatibility complex (MHC) proteins, a process known as self recognition, and (2) they must lack reactivity to peptide fragments from the proteins, a condition known as self-tolerance. B cells also display self-tolerance. Loss of self-tolerance leads to the development of autoimmune diseases.

Pre-T cells in the thymus develop the capability for self- recognition via positive selection. In this process, some pre-T cells express T-cell receptors (TCRs) that interact with self-MHC proteins on epithelial cells in the thymic cortex. Because of this interaction, the T cells can recognize the MHC part of an antigen-MHC complex. These T cells survive. Other immature T cells that fail to interact with thymic epithelial cells are not able to recognize self-MHC proteins. These cells undergo apoptosis.

The development of self-tolerance occurs by a weeding-out process called negative selection in which the T cells interact with nodular dendritic cells located at the junction of the cortex and medulla in the thymus. In this process, T cells with receptors that recognize self-peptide fragments or other self-antigens are eliminated or inactivated. The T cells selected to survive do not respond to self-antigens, the fragments of molecules that are normally present in the body. Negative selection occurs via both deletion and anergy. In deletion, self-reactive T cells undergo apoptosis and die; in anergy they remain alive but are unresponsive to antigenic stimulation. Only 1-5% of the immature T cells in the thymus receive the proper signals to survive apoptosis during both positive and negative selection and emerge as mature, immunocompetent T cells.

Once T cells have emerged from the thymus, they may still encounter an unfamiliar self-protein; in such cases they may also become anergic if there is no costimulator. Deletion of self-reactive T cells may also occur after they leave the thymus. B cells also develop tolerance through deletion and anergy. While B cells are developing in bone marrow, those cells exhibiting antigen receptors that recognize common self-antigens (such as MHC proteins or blood group antigens) are deleted. Once B cells are released into the blood, however, anergy appears to be the main mechanism for preventing responses to self-proteins. When B cells encounter an antigen not associated with an antigen-presenting cell, the necessary costimulation signal often is missing. In this case, the B cell is likely to become anergic (inactivated) rather than activated.

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