*Central and/or Intrathymic Tolerance*

The chief mechanism of T-cell tolerance is the deletion of autoreactive T cells in the thymus, rendering the organism tolerant to "self." Immature T cells migrate from the bone marrow to the thymus, where they encounter peptides derived from endogenous proteins that are bound to major histocompatibility complex (MHC) molecules on thymic epithelial cells.

Double-positive (CD4+ and CD8+) thymocytes initially undergo random generation of different T-cell receptors (TCRs). Positive selection, also called thymic education, ensures that only clones with TCRs that exhibit moderate affinity for self-MHC are allowed to develop. Negative selection by means of apoptosis occurs when T cells do not produce functional TCRs, when TCR rearrangement fails, when T cells have low affinity for MHCself-peptide complexes, or when T cells have extremely high affinity for such complexes. Negative selection also results in the deletion of some thymocytes that interact with autoantigens presented by interdigitating cells and macrophages at the corticomedullary junction. The remaining cells lose either CD4 or CD8 and leave the thymus to function in the periphery as mature, functional CD4+ and CD8+ T cells[31].
