The principal mechanism of central tolerance is the antigen-induced deletion (death) of self-reactive T lymphocytes and B lymphocytes during their maturation in central (generative) lymphoid organs (i.e., in the thymus for T cells and in the bone marrow for B cells). In the thymus, many autologous (self) protein antigens are processed and presented by thymic APCs. Any immature T cell that encounters such a self antigen undergoes apoptosis (a process called deletion, or negative selection), and the T cells that complete their maturation are thereby depleted of self-reactive cells. An exciting advance has been the identification of a protein called AIRE (autoimmune regulator), which stimulates expression of some peripheral tissue-restricted self antigens in the thymus and is thus critical for deletion of immature T cells specific for these antigens. Mutations in the AIRE gene are the cause of an autoimmune polyendocrinopathy (Chapter 20). Not all immature T cells that see self antigens in the thymus are deleted. Some CD4+ T cells survive and develop into regulatory T cells (described later).
Immature B cells that recognize self antigens with high affinity in the bone marrow also may die by apoptosis. Other self-reactive B cells are not deleted but instead undergo a second round of rearrangement of antigen receptor genes and then express new receptors that are no longer self-reactive (a process called receptor editing).
Central tolerance, however, is imperfect. Not all self antigens are present in the thymus or bone marrow, and hence lymphocytes bearing receptors for such autoantigens escape into the periphery. Self-reactive lymphocytes that escape negative selection can inflict tissue injury unless they are eliminated or muzzled in the peripheral tissues.
Several mechanisms silence potentially autoreactive T cells and B cells in peripheral tissues; these are best defined for T cells. These mechanisms include the following: • Anergy. This term refers to functional inactivation (rather than death) of lymphocytes that is induced by encounter with antigens under certain conditions. As described previously, activation of T cells requires two signals: recognition of peptide antigen in association with MHC molecules on APCs, and a set of second costimulatory signals (e.g., through B7 molecules) provided by the APCs. If the costimulatory signals are not delivered, or if an inhibitory receptor on the T cell (rather than the costimulatory receptor) is engaged when the cell encounters self antigen, the T cell becomes anergic and cannot respond to the antigen. Because costimulatory molecules are expressed at low levels or not at all on APCs presenting self antigens, the encounter between autoreactive T cells and self antigens in tissues may result in anergy.
It is believed that if mature B cells encounter self antigen in peripheral tissues, especially in the absence of specific helper T cells, these B cells become unable to respond to the antigen. B lymphocytes also express inhibitory receptors that may play a role in limiting their activation and preventing responses to  self antigens.
Suppression by regulatory T cells. A population of T cells called regulatory T cells functions to prevent immune reactions against self antigens. Regulatory T cells develop mainly in the thymus, but they also may be induced in peripheral lymphoid tissues. The best-defined regulatory T cells are CD4+ cells that express high levels of CD25, the α chain of the IL-2 receptor, and a transcription factor of the forkhead family, called FOXP3. Both IL-2 and FOXP3 are required for the development and maintenance of functional CD4+ regulatory T cells. Mutations in the FOXP3 gene result in severe autoimmunity in humans and mice; in humans, these mutations are the cause of a systemic autoimmune disease called IPEX (an acronym for immune dysregulation, polyendocrinopathy, enteropathy, X-linked).